Re: 파킨슨 병 .후각소실 2024년 논문...

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Neural Regen Res. 2024 Mar; 19(3): 583–590.

Published online 2023 Jul 20. doi: 10.4103/1673-5374.380875

PMCID: PMC10581567

PMID: 37721288

Olfactory dysfunction and its related molecular mechanisms in Parkinson’s disease

Yingying Gu, Jiaying Zhang, Xinru Zhao, Wenyuan Nie, Xiaole Xu, Mingxuan Liu,* and Xiaoling Zhang, MD*

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Abstract

Changes in olfactory function are considered to be early biomarkers of Parkinson’s disease. Olfactory dysfunction is one of the earliest non-motor features of Parkinson’s disease, appearing in about 90% of patients with early-stage Parkinson’s disease, and can often predate the diagnosis by years. Therefore, olfactory dysfunction should be considered a reliable marker of the disease. However, the mechanisms responsible for olfactory dysfunction are currently unknown. In this article, we clearly explain the pathology and medical definition of olfactory function as a biomarker for early-stage Parkinson’s disease. On the basis of the findings of clinical olfactory function tests and animal model experiments as well as neurotransmitter expression‎ levels, we further characterize the relationship between olfactory dysfunction and neurodegenerative diseases as well as the molecular mechanisms underlying olfactory dysfunction in the pathology of early-stage Parkinson’s disease. The findings highlighted in this review suggest that olfactory dysfunction is an important biomarker for preclinical-stage Parkinson’s disease. Therefore, therapeutic drugs targeting non-motor symptoms such as olfactory dysfunction in the early stage of Parkinson’s disease may prevent or delay dopaminergic neurodegeneration and reduce motor symptoms, highlighting the potential of identifying effective targets for treating Parkinson’s disease by inhibiting the deterioration of olfactory dysfunction.

초록

후각 기능의 변화는

파킨슨병의 초기 바이오마커로

간주됩니다.

후각 기능 장애는

파킨슨병의 가장 초기에 나타나는 비운동성 증상 중 하나로,

초기 파킨슨병 환자의 약 90%에서 나타나며

진단보다 몇 년 앞서 나타나는 경우가 많습니다.

따라서

후각 기능 장애는

파킨슨병의 신뢰할 수 있는 지표로 간주되어야 합니다.

그러나 후각 기능 장애를 일으키는 메커니즘은 현재 밝혀지지 않았습니다. 이 글에서는 초기 파킨슨병의 바이오마커로서 후각 기능의 병리와 의학적 정의를 명확하게 설명합니다.

또한

임상 후각 기능 검사 및 동물 모델 실험의 결과와 신경전달물질 발현 수준을 바탕으로

후각 기능 장애와 신경 퇴행성 질환의 관계,

초기 파킨슨병의 병리에서

후각 기능 장애의 기저에 있는 분자적 메커니즘을 규명합니다.

이 리뷰에서 강조된 연구 결과는

후각 기능 장애가 전임상 단계 파킨슨병의 중요한 바이오마커라는 것을 시사합니다.

따라서

파킨슨병 초기에

후각 기능 장애와 같은 비운동 증상을 표적으로 하는 치료제는

도파민성 신경 변성을 예방하거나 지연시키고

운동 증상을 감소시킬 수 있으며,

후각 기능 장애의 악화를 억제함으로써

파킨슨병 치료에 효과적인 표적을 발굴할 수 있는 가능성을 제시하고 있습니다.

Keywords: biomarker, early-stage, olfactory disorders, olfactory dysfunction, Parkinson’s disease

Introduction

In addition to the main motor symptoms that characterize Parkinson’s disease (PD), olfactory dysfunction (OD) is a non-motor symptom that affects more than 90% of patients early in the course of the disease and has recently been accepted as a supportive diagnostic marker (Berg et al., 2015; Iannilli et al., 2017; Slabik and Garaschuk, 2023). The appearance of OD, combined with disorders of the digestive tract and cardiovascular and autonomic nervous systems, has led to the notion that PD is a systemic disease. If this multisystem disorder is defined in terms of α-synuclein-related pathology, it can be considered that it begins at least within the brain from the olfactory bulb (OB), the associated anterior olfactory nucleus, and the dorsal motor nucleus complex of the glossopharyngeal and vagus nerves, and only later involves the nigrostriatal motor complex (Rey et al., 2016). Olfactory loss is considered one of the earliest preclinical signs of neurodegenerative disease, appearing a decade or more before the onset of cognitive and motor symptoms. Exposure of the olfactory system to the external environment makes it more susceptible to mechanical damage and trauma, which can lead to degenerative neuroinflammation (Bathini et al., 2019). The inability to detect odors and the diminished perception of harmful factors in the environment increases the risk of pathogens and toxins leaking into the brain through the olfactory system (Rey et al., 2018). Standardized tests of odor-recognition ability are widely used and may serve as useful tools for cognitive-level diagnosis and accurate disease prediction in older adults (Devanand, 2016).

The normal aging process is accompanied by OD, and the risk of OD increases with age during the development of PD pathology (Mullol et al., 2012). Self-testing the presence of reduced olfactory function is difficult in elderly people. Although the pathogenetic factors underlying OD remain unknown, the association of neurodegenerative diseases with aging, smoking, excessive alcohol consumption, and sinus disease is undeniable (Hummel et al., 2016; Kondo et al., 2020). The relationship between OD and neurodegenerative diseases is gradually gaining importance and research interest, making it crucial to explore the mechanisms of OD and reveal its link to neurodegenerative diseases. The high preval‎ence of olfactory impairment in PD and the ease of manipulating data for detection and statistics have led researchers to investigate olfaction as a biomarker for PD and thereby gain new research advances (Dan et al., 2021). This review combines the findings from clinical olfactory testing studies, animal simulation experiments, and neurotransmitter expression‎ level analyses to analyze the potential role of OD as an early biomarker of PD, with a particular focus on the molecular mechanisms associated with OD and early pathological conditions underlying PD.

소개

파킨슨병(PD)을 특징짓는 주요 운동 증상 외에도 

후각 기능 장애(OD)는 

질병 초기에 환자의 90% 이상에 영향을 미치는 비운동 증상이며 

최근 보조 진단 마커로 받아들여지고 있습니다(Berg et al., 2015; Iannilli et al., 2017; Slabik and Garaschuk, 2023). 

소화관 장애, 심혈관계 및 자율신경계 장애와 결합된 

과민성 대장증후군의 출현으로 인해 

PD는 전신 질환이라는 개념이 생겨났습니다. 

이 다계통 장애 multisystem disorder 를 

α-시누클린 관련 병리의 관점에서 정의하면, 

적어도 뇌 내에서 후각구(OB), 관련 전후각핵, 설인두 및 미주신경의 등운동핵 복합체에서 시작하여 

나중에야 비후각 운동 복합체를 포함하는 것으로 간주할 수 있습니다(Rey et al., 2016). 

후각 상실은 

인지 및 운동 증상이 나타나기 

10년 이상 전에 나타나는 

신경 퇴행성 질환의 

가장 초기 전임상 징후 중 하나로 간주됩니다. 

후각 시스템이 외부 환경에 노출되면 

기계적 손상과 외상에 더 취약해져 

퇴행성 신경 염증을 일으킬 수 있습니다(Bathini et al., 2019). 

냄새를 감지하지 못하고 

환경의 유해 요인에 대한 인식이 저하되면 

후각 시스템을 통해 

병원균과 독소가 

뇌로 누출될 위험이 높아집니다(Rey et al., 2018). 

냄새 인지 능력에 대한 표준화된 테스트가 널리 사용되고 있으며 

노인의 인지 수준 진단과 

정확한 질병 예측에 유용한 도구로 사용될 수 있습니다(Devanand, 2016).

정상적인 노화 과정에는 후각 장애가 동반되며, 

후각 장애의 위험은

 PD 병리가 발달하는 동안 

나이가 들면서 증가합니다(Mullol et al., 2012). 

노인의 경우 

후각 기능 저하 여부를 자가 테스트하는 것은 

어렵습니다. 

OD의 근본적인 병인 요인은 아직 밝혀지지 않았지만 

신경 퇴행성 질환과 

노화, 흡연, 과도한 음주 및 부비동 질환의 연관성은 부인할 수 없습니다(Hummel et al., 2016; Kondo et al., 2020). 

후각장애와 신경퇴행성 질환의 관계는 

점차 그 중요성과 연구적 관심이 높아지고 있어 

후각장애의 기전을 탐구하고 

신경퇴행성 질환과의 연관성을 밝히는 것이 중요해지고 있습니다. 

파킨슨병에서 후각 장애의 높은 유병률과 탐지 및 통계를 위한 데이터 조작의 용이성으로 인해 연구자들은 후각을 파킨슨병의 바이오마커로 조사하여 새로운 연구 진전을 이루었습니다(Dan et al., 2021). 이 리뷰에서는 임상 후각 테스트 연구, 동물 시뮬레이션 실험, 신경전달물질 발현 수준 분석 결과를 결합하여 후각이 PD의 초기 바이오마커로서의 잠재적 역할을 분석하고, 특히 후각과 관련된 분자 메커니즘 및 PD의 기저 병리 상태에 중점을 두고 있습니다.

Search Strategy

The authors searched the PubMed and Web of Science databases using the following terms for relevant articles published between January 2016 and December 2022: “olfactory disorders,” “early Parkinson’s biomarkers,” “oxidative stress,” “mitochondrial damage,” and “inflammatory factors.” Article screening and identification were performed by eval‎uating the title and abstract, and additional articles were identified by searching the reference lists of the selected articles. The types of articles selected in this review included literature reviews, studies describing clinical olfactory tests, and those reporting animal simulation experiments.

검색 전략
저자는 2016년 1월부터 2022년 12월 사이에 발표된 관련 논문에 대해 "후각 장애", "초기 파킨슨병 바이오마커", "산화 스트레스", "미토콘드리아 손상", "염증 인자" 등의 검색어를 사용하여 PubMed 및 Web of Science 데이터베이스를 검색했습니다. 논문 선별 및 식별은 제목과 초록을 평가하여 수행했으며, 선정된 논문의 참고문헌 목록을 검색하여 추가 논문을 확인했습니다. 이 검토에서 선정된 논문의 유형에는 문헌 고찰, 임상 후각 테스트를 설명하는 연구, 동물 시뮬레이션 실험을 보고한 논문이 포함되었습니다.

The Pathological Processes Underlying Olfactory Function

Methods of detecting olfactory function

Olfaction is a sensation that is coordinated by the olfactory nervous system and the trigeminal nervous system, which can perceive chemical stimuli at a distance (Tremblay and Frasnelli, 2018). Non-motor symptoms, including anterior olfactory nucleus OD, affect patients’ quality of life and are easily overlooked; for example, some PD patients are unaware of the presence of OD prior to testing (Li et al., 2010; Doty, 2017). Tests of olfactory ability typically include four panels assessing odor identification, discrimination, sensitivity, and habituation (Dan et al., 2021).

In odor-identification tests, participants identify and correctly name the odors presented in a test based on their perception (Krismer et al., 2017). In contrast, odor-discrimination tests eval‎uate the ability to distinguish between two or more odors and are similar to odor-recognition tests (Fullard et al., 2017), but with a focus on distinguishing significant or subtle differences in odors. Odor sensitivity refers to the ability to detect odors at a given different concentration, wherein the lowest concentration is determined to be the threshold; these tests are also known as odor-threshold tests (Trimmer et al., 2019). Furthermore, odor-habituation tests eval‎uate the temporary decrease in the ability to perceive odors after repeated or prolonged exposure to an odor or odor mixture (Pellegrino et al., 2017).

In neurodegenerative diseases, the most common methods to detect olfactory function by odor-identification tests are the University of Pennsylvania Odor Identification Test and the Sniffin’ Sticks Test (Marin et al., 2018). The Sniffin’ Sticks Test uses a pen-like device that is also suitable for odor discrimination and determination of odor thresholds because of its quick operation and rapid results (Hüttenbrink et al., 2013; Doty, 2015). Despite the availability of generally accepted methods for olfactory testing, there is a need to promote and encourage new measurement strategies and data analysis definitions. Recent experiments have used the electrobulbogram (EBG), a non-invasive measure of OB function (Iravani et al., 2020), to separate PD patients from age-matched controls. In these studies, spectrograms of EBG measurements were used to assess the differences in odor processing between PD patients and controls. Six specific EBG components were identified by discovering synchronization patterns that differed between PD and control groups. The use of these EBG components allowed for slightly better test results than clinical odor-identification tests while maintaining similar levels of sensitivity and in-sample error prediction (Iravani et al., 2021). Again, these EBG components correlated with disease characteristic specificity and the late components correlated with olfactory testing (Iravani et al., 2020, 2021).

Assessments of olfactory thresholds in patients with idiopathic PD has shown that the trigeminal pathway is less impaired than the olfactory system (Foguem et al., 2018). On the basis of the assertion that PD patients maintain trigeminal sensitivity, a subsequent study hypothesized the existence of specific functional connections between the trigeminal and olfactory processing areas in PD patients (Tremblay et al., 2019), and functional connectivity of the OD and altered chemosensory network patterns were further identified as possible mechanisms (Tremblay et al., 2020). Due to the possible information exchange between the olfactory system and the trigeminal nerve, the interaction patterns between the two chemosensory systems in patients with PD and non-Parkinsonian olfactory disorder were further elaborated at the level of the nasal mucosa, OB, and central nervous system (Tremblay and Frasnelli, 2021). Current methods applied to assess trigeminal sensitivity are time-consuming and imprecise, rendering them unsuitable for clinical screening. Therefore, the development of practical tools for measuring the trigeminal system to differentiate PD from non-Parkinsonian forms of olfactory impairment holds greater promise for application (Huart et al., 2019; Tremblay et al., 2019).

후각 기능의 근간이 되는 병리학적 과정
후각 기능을 감지하는 방법

후각은 

후각 신경계와 

삼차 신경계에 의해 조정되는 감각으로, 

원거리에서 화학 자극을 감지할 수 있습니다(Tremblay와 Frasnelli, 2018). 

전후각핵 OD를 포함한 비운동성 증상은 

환자의 삶의 질에 영향을 미치며 간과하기 쉬운데, 

예를 들어 일부 PD 환자는 

검사 전에 전후각핵의 존재를 인지하지 못하기도 합니다(Li et al., 2010; Doty, 2017). 

후각 능력 테스트에는 

일반적으로 냄새 식별, 변별, 민감도 및 습관화를 평가하는 

네 가지 패널이 포함됩니다(Dan et al., 2021).

odor identification, discrimination, sensitivity, and habituation

냄새 식별 테스트 odor identification 에서 참가자는 

자신의 지각에 따라 테스트에 제시된 

냄새를 식별하고 

정확한 이름을 지정합니다(Krismer et al., 2017). 

반면, 

냄새 변별  odor discrimination 테스트는 

두 가지 이상의 냄새를 구별하는 능력을 평가하는 것으로 

냄새 인식 테스트와 유사하지만(Fullard et al., 2017), 

냄새의 현저하거나 미묘한 차이를 구별하는 데 중점을 둡니다. 

냄새 민감도 odor sensitivity는 

주어진 다양한 농도에서 냄새를 감지하는 능력을 말하며, 

가장 낮은 농도가 역치로 결정되며 

이러한 테스트는 냄새 역치 테스트라고도 합니다(Trimmer et al., 2019). 

또한, 

냄새 습관화 odor habituation 테스트는 

냄새 또는 냄새 혼합물에 반복적으로 또는 장기간 노출된 후 

냄새를 인지하는 능력이 일시적으로 감소하는 것을 평가합니다(Pellegrino et al., 2017).

신경 퇴행성 질환에서 냄새 식별 테스트를 통해 후각 기능을 감지하는 가장 일반적인 방법은 펜실베니아 대학교 냄새 식별 테스트와 스니핑 스틱 테스트입니다(Marin et al., 2018). 스니핑 스틱 테스트는 펜과 같은 장치를 사용하는데, 빠른 작동과 빠른 결과로 인해 냄새 감별 및 냄새 역치 결정에도 적합합니다(Hüttenbrink et al., 2013; Doty, 2015). 후각 테스트에 일반적으로 인정되는 방법이 있음에도 불구하고 새로운 측정 전략과 데이터 분석 정의를 홍보하고 장려할 필요가 있습니다. 

최근 실험에서는 

비침습적인 후각 기능 측정 방법인 근전도(EBG)를 사용하여(Iravani et al., 2020) 

연령이 일치하는 대조군으로부터 PD 환자를 구분하는 실험이 진행되었습니다. 

이 연구에서는 EBG 측정 스펙트로그램을 사용하여 PD 환자와 대조군 간의 냄새 처리의 차이를 평가했습니다. PD 그룹과 대조군 간에 서로 다른 동기화 패턴을 발견하여 6가지 특정 EBG 성분을 확인했습니다. 이러한 EBG 구성 요소를 사용하면 비슷한 수준의 감도와 샘플 내 오류 예측을 유지하면서 임상 냄새 식별 테스트보다 약간 더 나은 테스트 결과를 얻을 수 있었습니다(Iravani 외., 2021). 다시 말하지만, 이러한 EBG 구성 요소는 질병 특성 특이성과 상관관계가 있었고 후기 구성 요소는 후각 테스트와 상관관계가 있었습니다(Iravani 외., 2020, 2021).

특발성 PD 환자의 후각 역치를 평가한 결과 

삼차 경로가 

후각 시스템보다 덜 손상된 것으로 나타났습니다(Foguem et al., 2018). 

PD 환자가 삼차신경 민감도를 유지한다는 주장에 근거하여, 

후속 연구에서는 PD 환자의 삼차신경과 후각 처리 영역 사이에 

특정 기능적 연결이 존재한다는 가설을 세웠으며(Tremblay et al., 2019), 

OD의 기능적 연결과 변화된 화학감각 네트워크 패턴이 가능한 메커니즘으로 추가로 확인되었습니다(Tremblay et al., 2020). 

후각 시스템과 삼차신경 사이의 정보 교환 가능성으로 인해 

파킨슨병과 비파킨슨병 후각 장애 환자에서 

두 화학감각 시스템 간의 상호작용 패턴은 

코 점막, OB 및 중추신경계 수준에서 더욱 정교해졌습니다(Tremblay와 Frasnelli, 2021). 

현재 삼차 민감도를 평가하는 데 적용되는 방법은 시간이 오래 걸리고 정확도가 떨어져 임상 검사에 적합하지 않습니다. 따라서 파킨슨병이 아닌 형태의 후각 장애와 PD를 구별하기 위해 삼차 신경계를 측정하는 실용적인 도구를 개발하는 것이 더 큰 가능성을 가지고 있습니다(Huart et al., 2019; Tremblay et al., 2019).

Signaling processes in the olfactory system

Anatomically, the olfactory nerves transmit olfactory impulses to the OBs, and a lesion in any part of the olfactory system can lead to interruptions in conduction (Smith and Bhatnagar, 2019). Previous studies attempted to identify the OB as one of the possible lesion areas in early olfactory impairment in PD (Marin et al., 2018; Zhang et al., 2020), and although the underlying mechanism remains unclear, the OB could be explored as a target area for related signaling pathways. Experimental measurements of the OB structure and surrounding areas showed reduced OB volume in PD patients (Wang et al., 2011), suggesting that the OB could also be used as a target for early symptomatic drug delivery.

The OB is a structure that processes odor information and contains many olfactory receptors (ORs) where olfactory axons extending from the nasal cavity transmit olfactory information to neurons, the last stage before the olfactory information reaches the cerebral cortex (Bathini et al., 2019). In humans, for example, odor molecules enter the nasal cavity and come into contact with ORs located on the cilia or synapses of olfactory sensory neurons (Figure 1). The binding of odor molecules to the ORs triggers a G-coupling protein-mediated intracellular signaling cascade (Shirasu et al., 2014). Cyclic-adenosine monophosphate (cAMP) opens cyclic nucleotide-gated ion channels, allowing calcium and sodium ions to enter the cell, causing depolarization of OR neurons and eventually leading to the creation of action potentials (Imai and Sakano, 2007).

후각 시스템의 신호 전달 과정

해부학적으로 후각 신경은

후각 자극을 OB에 전달하며,

후각 시스템의 어느 부위에 병변이 생기면

전도가 중단될 수 있습니다(Smith and Bhatnagar, 2019).

이전 연구에서는 OB를 PD의 초기 후각 장애에서 가능한 병변 영역 중 하나로 확인하려고 시도했으며(Marin et al., 2018; Zhang et al., 2020), 근본적인 메커니즘은 아직 명확하지 않지만 관련 신호 경로의 표적 영역으로 OB를 탐색할 수 있습니다. OB 구조와 주변 영역을 실험적으로 측정한 결과, PD 환자에서 OB 부피가 감소한 것으로 나타났는데(Wang et al., 2011), 이는 OB가 초기 증상 약물 전달의 표적으로도 사용될 수 있음을 시사합니다.

OB는 냄새 정보를 처리하는 구조로,

비강에서 뻗어 나온 후각 축삭이 후각 정보를

대뇌 피질에 도달하기 전 마지막 단계인 뉴런에 전달하는

후각 수용체(OR)가 많이 포함되어 있습니다(Bathini et al., 2019).

예를 들어 사람의 경우

냄새 분자는 비강으로 들어가

후각 감각 뉴런의 섬모 또는 시냅스에 위치한 OR과 접촉합니다(그림 1).

냄새 분자가

OR에 결합하면

G-커플링 단백질 매개 세포 내 신호 캐스케이드가 촉발됩니다(Shirasu et al., 2014).

순환 아데노신 모노포스페이트(cAMP)는

순환 뉴클레오티드-게이티드 이온 채널을 열어

칼슘과 나트륨 이온이 세포로 유입되어

OR 뉴런의 탈분극을 유발하고

결국 활동 전위를 생성하게 합니다(Imai and Sakano, 2007).

Figure 1

The process of olfactory transmission.

Each olfactory receptor is translated from a specific gene, and a large number of different odor receptors exist on the cilia or synapses to distinguish different odors. Most odor molecules will activate more than one odor receptor; similarly, each odor receptor will be activated by many similar odor structures. The large number of permutations between odor molecules and receptors allows the olfactory receptor system to detect and distinguish large numbers of odor molecules. Created with smart.servier.com and Microsoft PowerPoint 2021. OB: Olfactory bulbs; OE: olfactory epithelium.

후각이 전달되는 과정.

각 후각 수용체는 특정 유전자로부터 번역되며, 

섬모나 시냅스에는 서로 다른 냄새를 구별하기 위해

 수많은 다른 냄새 수용체가 존재합니다. 

대부분의 냄새 분자는 하나 이상의 냄새 수용체를 활성화하며, 마찬가지로 각 냄새 수용체는 많은 유사한 냄새 구조에 의해 활성화됩니다. 냄새 분자와 수용체 사이의 순열이 많기 때문에 후각 수용체 시스템은 많은 수의 냄새 분자를 감지하고 구별할 수 있습니다. 

smart.servier.com 및 Microsoft PowerPoint 2021으로 제작되었습니다. OB: 후각 전구; OE: 후각 상피.

In order to elucidate the process of information transmission in the olfactory system, we provide a brief description of the structure of the OB. The axons of olfactory sensory neurons connect to the glomerular layer composed of juxtaglomerular cells, forming the outermost layer of the OB, and then in order from the outside to the inside are the outer plexiform layer composed of tufted cells, the mitral cell layer composed of mitral cells, and the granule cell layer composed of granule cells (Nagayama et al., 2014). The neurons and their protrusions form complex synapses. Notably, coronal and fascicular cells act as projection neurons that send axons to the olfactory cortex to innervate secondary olfactory structures, including anterior olfactory nucleus, the pyriform cortex, the olfactory nodule, and the lateral internal olfactory cortex (Smith and Bhatnagar, 2019; Strauch et al., 2022). Anterior olfactory nucleus cells respond to odors; the pyriform cortex modifies the processing of odors based on experience and learning; and the olfactory nodules function to guide fastidious and valence-dependent odor responses (Rey et al., 2018). Neurons in secondary olfactory structures project to tertiary olfactory structures and transmit olfactory information to thalamic regions.

The olfactory system is connected to the external environment (Kondo et al., 2020). Once the ability to respond to harmful factors in the environment decreases, the possibility of direct exposure of the olfactory system to pathogens and toxic substances is greatly increased, becoming a suitable starting point for the development of olfactory lesions (Doty and Kamath, 2014). Since various tissues throughout the olfactory system not only work in concert with each other but are also closely connected to other non-olfactory brain regions, they may provide a gateway for the transmission of pathogens from the OB to the higher brain structures, where motor, cognitive, and other important functions are located (Georgiopoulos et al., 2019).

후각 시스템의 정보 전달 과정을 설명하기 위해 

후각 신경세포의 구조에 대해 간략하게 설명합니다. 

후각 감각 신경세포의 축삭은 

사구체세포로 구성된 사구체층에 연결되어 

OB의 가장 바깥쪽 층을 형성하고, 

바깥쪽에서 안쪽 순으로 술모양 세포로 구성된 

외연세포층, 승모세포로 구성된 승모세포층, 과립세포로 구성된 

과립세포층이 있습니다(Nagayama et al., 2014). 

The axons of olfactory sensory neurons connect to the glomerular layer composed of juxtaglomerular cells, forming the outermost layer of the OB, and then in order from the outside to the inside are the outer plexiform layer composed of tufted cells, the mitral cell layer composed of mitral cells, and the granule cell layer composed of granule cells (Nagayama et al., 2014). 

뉴런과 그 돌기는 복잡한 시냅스를 형성합니다. 특히, 관상세포와 돌기세포는 후각 피질로 축삭을 보내 전후각핵, 피리형 피질, 후각 결절, 측내후각피질 등 이차 후각 구조에 신경을 전달하는 투사 뉴런으로 작용합니다(Smith and Bhatnagar, 2019; Strauch et al., 2022). 

전후각핵 세포는 

냄새에 반응하고, 

피리형 피질은 경험과 학습에 따라 냄새 처리를 수정하며, 

후각 결절은 까다롭고 원자가 의존적인 냄새 반응을 유도하는 기능을 합니다(Rey et al., 2018). 

이차 후각 구조의 뉴런은 3차 후각 구조로 투사되어 후각 정보를 시상 영역으로 전달합니다.

후각 시스템은 외부 환경과 연결되어 있습니다(Kondo et al., 2020). 환경의 유해 요인에 대응하는 능력이 감소하면 후각 시스템이 병원균 및 독성 물질에 직접 노출 될 가능성이 크게 증가하여 후각 병변의 발병에 적합한 출발점이됩니다 (Doty and Kamath, 2014). 후각계 전체의 다양한 조직은 서로 협력하여 작용할 뿐만 아니라 다른 비후각 뇌 영역과도 밀접하게 연결되어 있기 때문에 병원균이 산후에서 운동, 인지 및 기타 중요한 기능이 있는 상부 뇌 구조로 전달되는 관문을 제공할 수 있습니다(Georgiopoulos et al., 2019).

Pathological manifestations accompanying olfactory impairment

The presence of Lewy’s bodies in the substantia nigra (SN) is a pathological hallmark of PD. In the current understanding of the development of PD pathology, Lewy bodies appear in the OB and subsequently extend to the rest of the nervous system (Lee et al., 2010). According to Braak staging, Lewy pathology begins in the OB and the dorsal motor nucleus of the vagus, consistent with the early appearance of OD (Braak et al., 2003). The pathological process then expands to other areas of the brain before reaching the SN.

α-Synuclein pathology has been reported to be present in the OB and related structures in PD patients with Lewy vesicles and in controls (Flores-Cuadrado et al., 2019; Chen et al., 2021; Agliardi et al., 2022; Gao et al., 2022; Sawamura et al., 2022). α-Synuclein is a presynaptic nerve terminal protein, the most common and important protein modification of which is phosphorylation (Emmanouilidou et al., 2010). α-Synuclein is phosphorylated primarily at the Ser129 site and can be observed in animal models of PD (Neumann et al., 2002; Chen and Feany, 2005). In non-PD brains, only 4% or less of α-synuclein is phosphorylated at this site (Anderson et al., 2006). This significant difference indicates that phosphorylation of α-synuclein at Ser129 is strictly controlled under healthy conditions and that phosphorylation occurs simultaneously with the presence of Lewy bodies in neuropathic conditions, promoting the accumulation of pathogenic α-synuclein. The mitochondria of SH-SY5Y cells and rat primary neurons are damaged by rotenone or 1-methyl-4-phenylpyridiniumion, and the influx of extracellular calcium increases, resulting in increased phosphorylation of Ser129, which is also regulated by the proteasome pathway (Arawaka et al., 2017). Phosphorylation of α-synuclein Ser129 is mediated by several kinases, including leucine-rich repeat kinase 2 (LRRK2) (Xu et al., 2022a). The two proteins can be colocalized in SN neurons and Lewy bodies in PD patients, but downregulation of LRRK2 expression‎ does not lead to significant differences in phosphorylated α-synuclein levels (Guerreiro et al., 2013).

Maintenance of the supply of synaptic vesicles at presynaptic terminals by aggregating synaptic vesicles has been shown to exert a regulatory role on dopamine (DA) release (Runwal and Edwards, 2021), which is essential for controlling the initiation and cessation of voluntary and involuntary movements. Elevated levels of α-synuclein may disrupt DA signaling (Runwal and Edwards, 2021). Increased DA release from the nigrostriatal terminals in mice is a manifestation of the lack of α-synuclein. Conversely, increased expression‎ of α-synuclein is associated with reduced DA reuptake and decreased DA transporter (DAT) function (Deeb et al., 2010), suggesting that α-synuclein may disrupt the normal function of DAT through some mechanism.

α-Synuclein has been proposed to bind to the lipid component of neuromelanin in nigrostriatal dopaminergic neurons to promote their self-aggregation (Yamada and Iwatsubo, 2018; Kurochka et al., 2021). The overexpression‎ and abnormal accumulation of α-synuclein results in continued progression of PD (Bousset et al., 2013; Dunning et al., 2013). In rodent experiments, α-synuclein protofibrils are microinjected into the OB, while the olfactory pathway could serve as a pathological vector for propagation to SN and other areas involved in the later stages of PD (Bhatia-Dey and Heinbockel, 2021). Selective regulation of glutamatergic neurotransmission alters extracellular α-synuclein levels, suggesting that this specific neural network is involved in the activity-dependent release mechanism of α-synuclein (Af Bjerkén et al., 2019). Although neuronal activity strictly regulates α-synuclein release, increased synaptic vesicle secretion is itself capable of eliciting α-synuclein release (Huang et al., 2019; Román-Vendrell et al., 2021).

Targeted drugs for reducing the abnormal accumulation of α-synuclein can be expected to treat the initial symptoms of neurodegenerative diseases. Depending on the evolution of α-synuclein accumulation, α-synuclein levels can be decreased by reduced synthesis and accumulation, increased degradation (Wong and Krainc, 2017), and other such approaches. Direct injection of siRNA in mice for one week reduces hippocampal and cortical α-synuclein levels, thereby achieving a reduction in its synthesis (McCormack et al., 2010). Although siRNA-mediated knockdown of α-synuclein has been shown to be effective in various PD models, its clinical application is limited by its inability to cross the blood-brain barrier and the plasma membrane of neurons (McCormack et al., 2010; Alarcón-Arís et al., 2018). Exosome-mediated antisense oligonucleotide 4 significantly reduces α-synuclein expression‎ and inhibits aggregation in primary neuronal cells and brains of α-syn A53T mice (Yang et al., 2021). There is an urgent need to identify substances that can also directly target α-synuclein, a consistent pathogen that has the potential to cross the blood-brain barrier and plasma membrane. Studies have shown that Tat-βsyn-degron peptide (an α-synuclein-targeting peptide) can specifically reduce α-synuclein levels in vitro and in vivo by influencing the intracellular endogenous proteasome degradation system and achieving stable degradation of α-synuclein within a few hours (Jin et al., 2021). Thus, this peptide not only shows high efficiency in knocking down α-synuclein, but also exerts neuroprotective effects by increasing the survival of dopaminergic neurons in animal models of PD.

후각 장애에 수반되는 병리학적인 증상

흑질(SN)에 루이체가 존재하는 것은

 PD의 병리학적인 특징입니다. 

현재 PD 병리의 발달에 대한 이해에서 

루이체는 

OB에 나타나고 

이후 나머지 신경계로 확장됩니다 (Lee et al., 2010). 

Braak 병기에 따르면, 

루이 병리학은 OD의 초기 출현과 일치하는

 OB와 미주 등쪽 운동 핵에서 시작됩니다 (Braak et al., 2003). 

그런 다음 

병리학적인 과정은 

SN에 도달하기 전에 뇌의 다른 영역으로 확장됩니다.

α-시누클레인 병리는 

루이소체가 있는 PD 환자 및 대조군에서 

OB 및 관련 구조에 존재하는 것으로 보고되었습니다(Flores-Cuadrado 등, 2019; Chen 등, 2021; Agliardi 등, 2022; Gao 등, 2022; Sawamura 등, 2022). 

α-시누클레인은 

시냅스 전 신경 말단 단백질로, 

가장 흔하고 중요한 단백질 변형은 인산화입니다(엠마누일리두 외., 2010). α-시누클레인은 주로 Ser129 부위에서 인산화되며 PD의 동물 모델에서 관찰할 수 있습니다(Neumann et al., 2002; Chen and Feany, 2005). 

https://www.nature.com/articles/s41419-023-05672-9

양친매성 반복을 특징으로 하는 N-말단(녹색)은 막과의 상호작용을 담당하고, 소수성 NAC(파란색)는 응집에 관여하며, 산성 C-말단(빨간색)은 Ca2+ 결합 및 샤프롱 유사 활성에 관여하는 등 알파-syn은 구조적으로 세 가지 모듈화된 영역으로 구성되어 있습니다. 낮은 농도의 Ca2+가 존재할 때 α-syn은 N-말단 영역만을 통해 지질 표면에 안정적으로 고정됩니다. Ca2+ 농도가 높으면 C-말단이 아닌 NAC 영역도 지질 결합 특성을 나타내며, 이는 세포막에 대한 α-syn의 친화성을 조절하는 데 다른 역할을 한다는 것을 시사합니다. B 왼쪽 패널: 제어 조건에서 α-syn은 세포외이동 과정에서 SNARE 복합체 형성 및 소포 도킹을 촉진하여 단백질 및 신경전달물질 방출을 조절하는 데 중요합니다. 세포 외 α-syn은 단일 시냅스에서 여러 세포 내 경로가 공존할 수 있으므로 빠른(즉, 키스 앤 런 모드) 및 느린(즉, 클라트린 매개 세포 내 이동, CME) 막 검색 모드를 통해 수용 뉴런에 영향을 줄 수 있습니다. 흥미롭게도 α-syn은 곡면 막을 감지하고 안정화시키는 역할로 인해 시냅스 소포의 CME와 관련이 있습니다. 오른쪽 패널: 생리적 조건(녹색)에서 α-syn은 구조화되지 않은 가용성 단량체와 사량체 형태 사이에서 균형을 이루는 다양한 형태로 존재합니다. 병리학적인 조건(연한 빨간색)에서 α-syn 생성과 제거 사이의 균형이 깨지면 α-syn은 올리고머, 원섬유, 원섬유로 응집되어 LB라는 단백질 내포물을 형성하게 됩니다.

비PD 뇌에서는

 α-시누클레인의 4% 이하만이 

이 부위에서 인산화됩니다(Anderson et al., 2006). 

이 중요한 차이는 

건강한 상태에서는 Ser129에서 α-시누클레인의 인산이 엄격하게 제어되고 

신경병증 상태에서는 루이체의 존재와 동시에 

인산이 발생하여 병원성 α-시누클레인의 축적을 촉진한다는 것을 나타냅니다. 

SH-SY5Y 세포와 쥐의 일차 뉴런의 미토콘드리아는 로테논 또는 1-메틸-4-페닐피리디늄 이온에 의해 손상되고 세포 외 칼슘의 유입이 증가하여 프로테아좀 경로에 의해 조절되는 Ser129의 인산화가 증가합니다(Arawaka et al., 2017). α-시누클레인 Ser129의 인산화는 류신 풍부 반복 키나아제 2(LRRK2)를 포함한 여러 키나아제에 의해 매개됩니다(Xu et al., 2022a). 두 단백질은 PD 환자의 SN 뉴런과 루이체에서 공동 위치할 수 있지만, LRRK2 발현의 하향 조절은 인산화 α-시누클레인 수치에 큰 차이를 초래하지 않습니다(Guerreiro et al., 2013).

시냅스 소포 응집에 의한 시냅스 전 단자에서의 시냅스 소포 공급 유지는 

자발적 및 비자발적 운동의 시작과 중단을 조절하는 데 필수적인 

도파민(DA) 방출에 조절 역할을 하는 것으로 나타났습니다(Runwal and Edwards, 2021). 

α-시누클레인 수치가 높아지면 

DA 신호가 방해받을 수 있습니다(Runwal and Edwards, 2021). 

생쥐의 흑질 말단에서 

DA 방출이 증가하면 

α-시누클레인이 부족하다는 것을 알 수 있습니다. 

반대로 α-시누클레인의 발현 증가는 

DA 재흡수 감소 및 DA 수송체(DAT) 기능 감소와 관련이 있으며(Deeb 등, 2010), 

이는 α-시누클레인이 어떤 메커니즘을 통해 

DAT의 정상적인 기능을 방해할 수 있음을 시사합니다.

α-시누클레인은 흑질 도파민성 뉴런에서 뉴로멜라닌의 지질 성분에 결합하여 자기 응집을 촉진하는 것으로 제안되었습니다(Yamada and Iwatsubo, 2018; Kurochka et al., 2021). α-시누클레인의 과발현과 비정상적인 축적은 PD의 지속적인 진행을 초래합니다(Bousset et al., 2013; Dunning et al., 2013). 설치류 실험에서 α-시누클레인 원섬유는 OB에 미세 주입되는 반면, 후각 경로는 SN 및 PD의 후기 단계에 관여하는 다른 영역으로 전파되는 병리학적인 벡터로 작용할 수 있습니다(Bhatia-Dey and Heinbockel, 2021). 글루탐산성 신경전달의 선택적 조절은 세포 외 α-시누클레인 수준을 변화시켜 이 특정 신경 네트워크가 α-시누클레인의 활동 의존적 방출 메커니즘에 관여한다는 것을 시사합니다(Af Bjerkén 외., 2019). 신경 세포 활동이 α-시누클레인 방출을 엄격하게 조절하지만, 시냅스 소포 분비 증가 자체가 α-시누클레인 방출을 유도할 수 있습니다(Huang et al., 2019; Román-Vendrell et al., 2021).

α-시누클레인의 비정상적인 축적을 줄이기 위한 표적 약물은 신경 퇴행성 질환의 초기 증상을 치료할 수 있을 것으로 기대할 수 있습니다. α-시누클레인 축적의 진화에 따라 합성과 축적을 줄이고 분해를 증가시켜 α-시누클레인 수치를 낮출 수 있으며(Wong and Krainc, 2017), 기타 이러한 접근법을 통해 α-시누클레인 수치를 낮출 수 있습니다. 생쥐에 일주일 동안 siRNA를 직접 주입하면 해마 및 피질 α-시누클레인 수치가 감소하여 합성이 감소합니다(McCormack et al., 2010). α-시누클레인의 siRNA 매개 녹다운은 다양한 PD 모델에서 효과적인 것으로 나타났지만, 혈액-뇌 장벽과 신경세포의 혈장막을 통과하지 못하기 때문에 임상 적용이 제한적입니다(McCormack et al., 2010; Alarcón-Arís et al., 2018). 엑소좀 매개 안티센스 올리고뉴클레오티드 4는 α-syn A53T 마우스의 일차 신경세포와 뇌에서 α-시누클레인 발현을 현저히 감소시키고 응집을 억제합니다(Yang et al., 2021). 혈액-뇌 장벽과 혈장막을 통과할 가능성이 있는 일관된 병원체인 α-시누클레인을 직접 표적으로 삼을 수 있는 물질을 찾는 것이 시급한 과제입니다. 연구에 따르면 Tat-βsyn-degron 펩타이드(α-시누클린 표적 펩타이드)는 세포 내 내인성 프로테아좀 분해 시스템에 영향을 미치고 몇 시간 내에 α-시누클린의 안정적인 분해를 달성함으로써 시험관 및 생체 내에서 α-시누클린 수준을 구체적으로 감소시킬 수 있습니다(Jin et al., 2021). 따라서 이 펩타이드는 α-시누클레인 분해에 높은 효율을 보일 뿐만 아니라 파킨슨병 동물 모델에서 도파민 신경세포의 생존을 증가시켜 신경 보호 효과도 발휘합니다.

Research Advances and Drug Discovery Related to Olfactory Dysfunction in Parkinson’s Disease

Alterations in neurotransmitter content

Relative stability among the levels of different neurotransmitters is crucial; for example, imbalance between the functions of the acetylcholine and DA systems can lead to serious neurological disorders (Oh et al., 2017). Once the DA level gradually decreases and its effect is diminished, the acetylcholine functional system becomes relatively excited, resulting in PD symptoms. Previous studies have shown OD to be an early biomarker of PD (Fullard et al., 2017), suggesting a unique link between the two. Although the exact mechanism of olfactory hyposmia in PD is unknown, altered levels of acetylcholine, DA, norepinephrine, and serotonin in different brain regions of PD patients may be associated with the presence of OD (Müller and Bohnen, 2013; Doty, 2017; Marin et al., 2018).

DA plays an important role in the pathogenesis of PD (Klein et al., 2019) and has received a great deal of attention as an important topic of study in relation to olfactory loss. The SN-striatal pathway is the pathway with the highest DA content, and a decrease in DA function in this pathway triggered by self-regulation or external stimuli can lead to PD (Bohnen et al., 2007). DA also innervates some structures of the olfactory system (Liu, 2020), such as the olfactory nodules, internal olfactory cortex, and pear-shaped cortex, in the midbrain-limbic and midbrain-cortical pathways, mainly regulating cognitive and perceptual abilities. OBs contain approximately 10% of dopaminergic interneurons in the glomerular layer. Dopaminergic interneurons are involved in olfactory processing and determine olfactory capacity, and DA receptors are expressed in the OB (Fullard et al., 2017; Klein et al., 2019). Studies have shown that the results of olfactory tests in PD patients correlate with decreased DAT activity in the SN, striatum, and hippocampus (Bohnen et al., 2007; Deeb et al., 2010). DAT is a structure located on the presynaptic membrane of DA neurons whose function is to enable the reuptake of DA released into the synaptic gap and buffer the level of released DA for normal physiological function of synapses (Bu et al., 2021). Dopaminergic neurons have been suggested to be highly plastic to olfactory pathway operation (Doty et al., 1992). However, olfaction has not been found to be responsive to dopaminergic replacement therapy. Whether alterations in DA levels are directly associated with olfactory hypoesthesia or whether there are common underlying mechanisms is unclear.

Several studies have shown that acetylcholine release and acetylcholine receptor activation play positive roles in olfactory learning, memory, and odor recognition (Mandairon et al., 2011; Devore et al., 2012). Notably, the association between changes in acetylcholine levels and olfactory impairment is not specific to PD and may be a common mechanism for OD in neurodegenerative diseases (Doty, 2017).

A third neurotransmitter that may play a role in the pathogenesis of olfactory impairment in PD is serotonin (Fullard et al., 2017). Serotonin is derived from the median suture nucleus, which sends projections to the OB. The glomerular layer contains a dense distribution of serotonergic fibers and is innervated by the median nucleus of the septum (Huang et al., 2017). The main role of serotonin in the OB is to regulate the activity of the mitral cells, which is mainly excitatory (Brill et al., 2016). In patients with PD, Lewy pathology is found in the median septal nucleus, along with a marked decrease in serotonin in OB and other regions of the olfactory system (Qamhawi et al., 2015; Vermeiren et al., 2018). Although the exact mechanism underlying these changes has not yet been determined, the observations suggest that alterations in serotonin may be associated with OD in PD.

파킨슨병의 후각 기능 장애와 관련된 연구 발전 및 신약 개발
신경전달물질 함량의 변화

예를 들어 

아세틸콜린과 DA 시스템의 기능 간 불균형은 

심각한 신경학적 장애를 초래할 수 있습니다(Oh et al., 2017). 

DA 수치가 점차 감소하고 그 효과가 감소하면 

아세틸콜린 기능 시스템이 상대적으로 흥분되어 

PD 증상이 나타납니다. 

이전 연구에 따르면 후각은 PD의 초기 바이오마커로 밝혀져(풀라드 등, 2017), 이 둘 사이에 독특한 연관성이 있음을 시사합니다. 

PD에서 후각 저감증의 정확한 메커니즘은 알려져 있지 않지만, 

PD 환자의 여러 뇌 영역에서 

아세틸콜린, DA, 노르에피네프린, 세로토닌의 변화된 수치가 

OD의 존재와 관련이 있을 수 있습니다(Müller and Bohnen, 2013; Doty, 2017; Marin et al., 2018).

DA는 

후각 상실과 관련하여 중요한 연구 주제로 많은 관심을 받고 있으며(Klein et al., 2019), 

PD의 발병 기전에서 중요한 역할을 합니다. 

SN- 선조체 경로는 DA 함량이 가장 높은 경로로, 

자기 조절 또는 외부 자극에 의해 유발된 이 경로에서

 DA 기능이 감소하면 PD로 이어질 수 있습니다(Bohnen et al., 2007). 

DA는 

또한 중뇌-변연계 및 중뇌-피질 경로에서 

후각 결절, 내부 후각 피질 및 배 모양 피질과 같은 후각 시스템의 일부 구조 (Liu, 2020)를 신경화하여 

주로인지 및 지각 능력을 조절합니다. 

OB는 

사구체층에 약 10%의 도파민성 뉴런을 포함하고 있습니다. 

도파민성 뉴런은 

후각 처리에 관여하고 

후각 능력을 결정하며, 

DA 수용체는 

OB에서 발현됩니다(Fullard et al., 2017; Klein et al., 2019). 

연구에 따르면 PD 환자의 후각 검사 결과는 SN, 선조체 및 해마의 DAT 활동 감소와 상관관계가 있는 것으로 나타났습니다(Bohnen et al., 2007; Deeb et al., 2010). DAT는 DA 뉴런의 시냅스 전막에 위치한 구조로, 시냅스 갭으로 방출된 DA의 재흡수를 가능하게 하고 시냅스의 정상적인 생리학적 기능을 위해 방출된 DA의 수준을 완충하는 기능을 합니다(Bu et al., 2021). 도파민성 뉴런은 후각 경로 작동에 매우 가소성이 있는 것으로 제안되었습니다(Doty et al., 1992). 그러나 후각은 도파민 대체 요법에 반응하지 않는 것으로 밝혀졌습니다. DA 수치의 변화가 후각 저하와 직접적으로 관련이 있는지 또는 일반적인 기저 메커니즘이 있는지는 불분명합니다.

여러 연구에 따르면 아세틸콜린 방출과 아세틸콜린 수용체 활성화는 후각 학습, 기억 및 냄새 인식에 긍정적인 역할을 하는 것으로 나타났습니다(Mandairon 외., 2011; Devore 외., 2012). 

특히 

아세틸콜린 수치의 변화와 후각 장애 사이의 연관성은 

파킨슨병에만 국한된 것이 아니며 

신경 퇴행성 질환에서 

후각 장애의 일반적인 메커니즘일 수 있습니다(Doty, 2017).

파킨슨병에서 

후각 장애의 발병에 관여할 수 있는 세 번째 신경전달물질은 

세로토닌입니다(Fullard et al., 2017). 

세로토닌은 

사구체 봉합핵에서 유래하며, 

사구체 봉합핵은 후두엽으로 투영을 보냅니다. 

사구체층에는 

세로토닌 섬유가 조밀하게 분포되어 있으며 

중격의 중앙핵에 의해 신경을 자극받습니다(Huang et al., 2017). 

OB에서 

세로토닌의 주요 역할은 

주로 흥분성 인 승모 세포의 활동을 조절하는 것입니다 (Brill et al., 2016). 

PD 환자에서 루이병은 

중격 중격핵에서 발견되며, 

OB 및 후각계의 다른 영역에서 세로토닌의 현저한 감소와 함께 발견됩니다(Qamhawi 외., 2015; Vermeiren 외., 2018). 

이러한 변화의 정확한 메커니즘은 아직 밝혀지지 않았지만, 

관찰 결과에 따르면 세로토닌의 변화는 

PD의 OD와 관련이 있을 수 있습니다.

Molecular mechanisms underlying the pathological processes in olfactory dysfunction

Autophagy plays an important role in life activities and is an essential process to maintain cellular homeostasis through phagocytosis and degradation of damaged, degenerated, senescent, and non-functional cellular components or degenerated biomolecules (Ichimiya et al., 2020). To safeguard the normal function of neurons and synapses, autophagy-centered protective mechanisms maintain high neurotransmission and the functional proteome integrity of neurons by removing toxins or unwanted cellular components (Bonam et al., 2021). Autophagy is age-related, and its dysfunction makes neurons more susceptible to stress, which leads to cell death (Stavoe et al., 2019). Oxidative stress, PD gene mutations, and overexpression‎ may affect α-synuclein conformational changes and its aggregation (Jankovic and Tan, 2020).

The presence of inflammatory factors in cells can trigger the process of autophagy; therefore, the occurrence of neuroinflammation exerts an important role in the pathological processes underlying neurodegenerative diseases. Microglia with neuroinflammation exert phagocytosis, preferentially activating at the OB site and affecting normal olfactory function (Lalancette-Hébert et al., 2009). One study found that intranasal lipopolysaccharide (LPS) infusion activates microglia in the OB, SN, and striatum (Niu et al., 2020). After activation, microglia produce many cytokines and upregulate the expression‎ levels of cell surface receptors and phagocytic receptors, which initiate the immune response (Tian et al., 2012). Microglial overactivation-mediated inflammatory responses are a common pathological feature of several neurological diseases, including PD (Lecours et al., 2018). The main features of LPS-induced inflammation include significant activation of Toll-like receptor 4 signaling and release of proinflammatory cytokines, including interleukin-1β (Skrzypczak-Wiercioch and Sałat, 2022). At the same time, interleukin-1β can act on neurons expressing interleukin-1 receptor 1 to cause neuropathology. Conversely, pathological α-synuclein transfer from the OB to the SN is reduced in the absence of interleukin-1 receptor 1 (Niu et al., 2020).

In a mouse model of rotenone-induced PD-like symptoms, microglial activation has also been observed to lead to cognitive impairment through neuroinflammation, oxidative stress, and apoptosis, with a preference for neuronal damage and abnormal α-synuclein accumulation (Zhang et al., 2021). Studies have reported that dysregulated microglial activation can increase the aggregation of pathological proteins and cause impaired synaptic pruning processes and neuronal plasticity (Czirr et al., 2017; Subhramanyam et al., 2019). Restraining microglial overactivation can help mitigate neuronal damage. Melatonin receptor 1 activation inhibits the microglial activation induced by inflammatory stimuli, including LPS, and alters the metabolic state to achieve the effect of protecting DA neurons from inflammatory damage (Gu et al., 2021). After the onset of the proinflammatory response, LPS stimulation leads to elevated LRRK2 protein levels and dynamin-related protein 1 (Drp1)-dependent mitochondrial division in microglia (Ho et al., 2018).

Mutations in the gene encoding LRRK2 have been shown to be associated with familial and sporadic PD (Bonam et al., 2021). Odor recognition appears to be significantly affected in PD patients carrying mutations in the LRRK2 gene. This can be reflected in the fact that the majority of PD patients with LRRK2 mutations exhibit subjective OD and hyposmia in olfactory test results (Ruiz-Martínez et al., 2011; Loeffler et al., 2019). LRRK2 affects function within the nucleus, while outside the nucleus, it triggers a state of autophagic/lysosomal stress by increasing protein translation and mitochondrial autophagy through inhibition of 4E-BP1 protein (Dastidar et al., 2020). However, it remains unclear whether LRRK2 mutations lead to abnormal development of DA neurons. The LRRK2-G2019 mutation shortens the differentiation and cell cycle of early neural stem cells and is critical for mediating the process of neural stem cell differentiation by affecting the downregulation of the transcription factor nuclear receptor subfamily 2 group F member 1 (Walter et al., 2021). The LRRK2-G2019S mutation has been demonstrated to accelerate the rate of differentiation of neural stem cells to dopaminergic neurons, along with an increase in apoptosis (Le Grand et al., 2015). However, the signaling pathway between LRRK2-G2019S and nuclear receptor subfamily 2 group F member 1 needs further investigation.

Lysosomes contain a variety of hydrolytic enzymes, the main function of which is to break down various exogenous or endogenous macromolecules, and all autophagic pathways more or less involve lysosomes (Ichimiya et al., 2020). ATPase cation transporting 13A2 (ATP13A2) protein is localized in some cellular acidic vesicles, including lysosomes and autophagosomes, and is primarily responsible for cation transport in lysosome-like vesicles. ATP13A2 mutations can be observed in early-onset PD (van Veen et al., 2020). An in vitro study confirmed that increasing ATP13A2 protein levels reduce α-synuclein-induced toxicity (Murphy et al., 2013). Heterozygous mutations in pathogenic ATP13A2 are known to cause defects in ATP13A2 expression‎ and mitochondrial dysfunction. Drug treatment that increases free zinc ion concentration exacerbates the loss of mitochondrial function with mitochondrial fragmentation and ATP depletion, leading to cell death (Park et al., 2014).

OD is also common in PTEN-induced putative kinase 1 (PINK1) gene-mediated PD (Ferraris et al., 2009), but its association with mitochondrial damage is not clear. Previous studies have suggested that mutations in genes associated with PD (e.g., Parkin RBR E3 ubiquitin protein ligase [PRKN], PINK1) or other factors leading to mitochondrial defects contribute to the pathogenesis of PD (Poole et al., 2008). Mitochondria are important organelles with multiple functions to meet the high energy requirements of neuronal cells. They also play crucial roles in regulating membrane potential, cell differentiation and apoptosis, and are actively recruited to the presynaptic membrane (Devine and Kittler, 2018). Studies have shown that mitochondrial dysfunction can lead to morphological and kinetic alterations, reduced energy production, alterations in mitochondrial DNA, production of reactive oxygen species (ROS), and abnormal calcium homeostasis, which are considered to be the underlying mechanisms of neuronal cell death in PD (Ammal Kaidery and Thomas, 2018). Cells selectively remove damaged mitochondria, enabling mitochondrial quality control and protecting cells by triggering autophagic mechanism, a process called mitochondrial autophagy. To maintain a healthy mitochondrial network, cells process damaged mitochondria through mitosis and generate new effective mitochondria (Anzell et al., 2018). Mitochondrial autophagy involves the activity of mitochondrial kinase PINK1 and cytoplasmic Parkin, which activates the PINK1/Parkin pathway (Pickrell and Youle, 2015).

Mutations in PINK1 may reduce mitochondrial activity and Parkin activation, and result in the inability of damaged mitochondria to separate by mitosis rupture (Deng et al., 2008). Interestingly, a link between PINK1 mutations, decreased Drp1 levels, and increased Drp1 GTPase activity suggests a direct induction of mitochondrial fission by PINK1 (Sandebring et al., 2009). PINK1 deficiency has also been shown to be associated with impaired sodium ion channels, leading to uncontrollable pre-existing mitochondrial calcium homeostasis (Gandhi et al., 2009). On the one hand, PINK1 dysfunction inhibits Mfn2 protein expression‎, leading to increased sensitivity of DA neuronal cells to neurotoxins (Peng et al., 2019). On the other hand, Parkin-mediated Mfn2 ubiquitination plays an important role in the formation of endoplasmic reticulum-mitochondrial contacts, which is essential for mitochondrial energy metabolism and calcium homeostasis (McLelland et al., 2018). Notably, Parkin preferentially binds to mitochondria, protects mitochondrial DNA from oxidative stress, and stimulates mitochondrial DNA repair (Rothfuss et al., 2009). In contrast, Parkin knockout mouse strains showed neurons in the ventral part of the midbrain, indicating severe mitochondrial damage and reduction of complexes I and IV, without exhibiting the motor deficits characteristic of PD (Palacino et al., 2004; Stichel et al., 2007).

Defects in the mitochondrial autophagic pathway, particularly PARK2 (PRKN mutation) and PARK6 (PINK1 mutation), are thought to be the main causes of familial PD (Wang et al., 2022). Under normal conditions, PINK1 localized in mitochondria is translocated to the inner mitochondrial membrane and degraded (Wang et al., 2020). However, under the influence of some hitherto unknown conditions, mitochondria are dysfunctional, resulting in loss of membrane potential. Damaged mitochondria activate PINK1 and uptake of PRKN, helping induce autophagy while acting on other mitochondrial membrane proteins (Heo et al., 2015). Parkin has been implicated in the proteasomal degradation of damaged mitochondria, and its mutations can lead to autosomal recessive forms of PD (Gandhi et al., 2009). Additionally, PRKN deficiency leads to the degeneration of DA neurons in mice, while PINK1 deficiency causes lysosomal dysfunction in mouse embryonic fibroblasts (Demers-Lamarche et al., 2016). Under normal conditions, damaged or functionally deficient mitochondria are surrounded and proteolyzed. However, during PD pathology, mutations in PINK1 and Parkin substantially reduce the clearance of damaged organelles. The accumulation of injured organelles is likely to be the ultimate cause of cell death (Anzell et al., 2018).

With increasing age or the induction of pathological factors, the mitochondrial DNA of microglia is damaged, and ROS appears inside the cell (von Bernhardi et al., 2015). ROS accumulation occurs mainly in the early stages of PD and occurs in many signaling pathways, and excess accumulation causes or accelerates cell death (Morris et al., 2018). Research on ROS has mainly focused on the DA release and metabolic processes in the SN-striatal pathway, and the DA of OB still needs to be studied. During oxidative phosphorylation, complex I acts as a catalyst for the transfer of electrons from nicotinamide adenine dinucleotide (NADH) to subunits of the electron transport chain and is considered to be the primary site for ROS production in the mitochondria (Wu et al., 2019). In mitochondrial complex I, high proton motility due to low ATP production or a high NADH/nicotinamide adenine dinucleotide (NAD+) ratio in the substrate tends to produce large amounts of superoxide radicals (Figure 2). Superoxide dismutase 2 converts superoxide radicals to hydrogen peroxide, which is further detoxified by peroxidase. However, in the presence of metal ions (Fe2+), hydrogen peroxide undergoes a Fenton reaction and is converted to highly reactive hydroxyl radicals, resulting in severe cellular oxidative damage (Murphy, 2009).

후각 기능 장애의 병리학적 과정의 기초가 되는 분자 메커니즘

자가포식은

생명 활동에서 중요한 역할을 하며

손상, 퇴화, 노화, 기능하지 않는 세포 성분이나 퇴화된 생체 분자를 포식하고 분해하여

세포 항상성을 유지하는 데 필수적인 과정입니다(Ichimiya et al., 2020).

뉴런과 시냅스의 정상적인 기능을 보호하기 위해

자가포식 중심의 보호 메커니즘은

독소나 불필요한 세포 성분을 제거하여

높은 신경 전달과 뉴런의 기능적 단백질체 무결성을 유지합니다(Bonam et al., 2021).

오토파지는

노화와 관련이 있으며,

기능 장애는 뉴런을 스트레스에 더 취약하게 만들어 세포 사멸로 이어집니다(Stavoe et al., 2019).

산화 스트레스,

PD 유전자 돌연변이,

과발현은 α-시누클레인 형태 변화와 응집에 영향을 미칠 수 있습니다(Jankovic and Tan, 2020).

세포에 염증 인자가 존재하면

자가포식 과정을 촉발할 수 있으므로

신경염증의 발생은 신경 퇴행성 질환의 기저에 있는 병리학적인 과정에서 중요한 역할을 합니다.

신경 염증이 있는 미세아교세포는

식균 작용을 하며,

우선적으로 OB 부위에서 활성화되고

정상적인 후각 기능에 영향을 미칩니다(Lalancette-Hébert 외., 2009).

한 연구에 따르면 비강 내 지질 다당류(LPS) 주입은 OB, SN 및 선조체에서 미세아교세포를 활성화하는 것으로 나타났습니다(Niu et al., 2020).

활성화 후 미세아교세포는

많은 사이토카인을 생성하고

세포 표면 수용체와 식세포 수용체의 발현 수준을 상향 조절하여

면역 반응을 개시합니다(Tian et al., 2012).

미세아교세포 과활성화 매개 염증 반응은

PD를 포함한 여러 신경 질환의 공통적인 병리학적 특징입니다(Lecours et al., 2018).

LPS 유발 염증의 주요 특징으로는 톨 유사 수용체 4 신호의 현저한 활성화와 인터루킨-1β를 포함한 전 염증성 사이토카인의 방출이 있습니다(Skrzypczak-Wiercioch and Sałat, 2022). 동시에 인터루킨-1β는 인터루킨-1 수용체 1을 발현하는 뉴런에 작용하여 신경 병리를 유발할 수 있습니다. 반대로, 인터루킨-1 수용체 1이 없으면 OB에서 SN으로의 병리학적인 α- 시누클레인 이동이 감소합니다(Niu et al., 2020).

로테논으로 유발된 PD 유사 증상의 마우스 모델에서 미세아교세포 활성화는 신경 염증, 산화 스트레스 및 세포 사멸을 통해 인지 장애로 이어지는 것으로 관찰되었으며, 신경 손상과 비정상적인 α-시누클레인 축적을 선호합니다(Zhang et al., 2021). 연구에 따르면 조절 장애가 있는 미세아교세포 활성화는 병적 단백질의 응집을 증가시키고 시냅스 가지치기 과정과 신경 가소성을 손상시킬 수 있다고 보고되었습니다(Czirr et al., 2017; Subhramanyam et al., 2019). 미세아교세포 과활성화를 억제하면 신경세포 손상을 완화하는 데 도움이 될 수 있습니다. 멜라토닌 수용체 1 활성화는 LPS를 포함한 염증 자극에 의해 유도된 미세아교세포 활성화를 억제하고 대사 상태를 변화시켜 염증성 손상으로부터 DA 신경세포를 보호하는 효과를 달성합니다(Gu et al., 2021). 전 염증 반응이 시작된 후, LPS 자극은 미세아교세포에서 LRRK2 단백질 수준과 다이나민 관련 단백질 1(Drp1)-의존성 미토콘드리아 분열을 증가시킵니다(Ho et al., 2018).

LRRK2를 암호화하는 유전자의 돌연변이는 가족성 및 산발성 PD와 관련이 있는 것으로 나타났습니다(Bonam et al., 2021). LRRK2 유전자에 돌연변이가 있는 PD 환자에서 냄새 인식이 크게 영향을 받는 것으로 보입니다. 이는 LRRK2 돌연변이를 가진 PD 환자의 대다수가 후각 검사 결과에서 주관적 후각과 후각 저하를 보인다는 사실에 반영될 수 있습니다(Ruiz-Martínez 외., 2011; Loeffler 외., 2019). LRRK2는 핵 내에서는 기능에 영향을 미치고, 핵 밖에서는 4E-BP1 단백질의 억제를 통해 단백질 번역과 미토콘드리아 자가포식을 증가시켜 자가포식/리소좀 스트레스 상태를 유발합니다(Dastidar et al., 2020). 그러나 LRRK2 돌연변이가 DA 뉴런의 비정상적인 발달로 이어지는지는 아직 불분명합니다. LRRK2-G2019 돌연변이는 초기 신경 줄기 세포의 분화와 세포주기를 단축하고 전사인자 핵 수용체 서브 패밀리 2 그룹 F 멤버 1의 하향 조절에 영향을 주어 신경 줄기 세포 분화 과정을 매개하는 데 중요합니다 (Walter et al., 2021). LRRK2-G2019S 돌연변이는 신경 줄기 세포의 도파민성 뉴런으로의 분화 속도를 가속화하고 세포 사멸을 증가시키는 것으로 입증되었습니다(Le Grand et al., 2015). 그러나 LRRK2-G2019S와 핵 수용체 서브 패밀리 2 그룹 F 멤버 1 사이의 신호 경로는 추가 조사가 필요합니다.

리소좀에는 다양한 가수분해 효소가 포함되어 있으며, 그 주요 기능은 다양한 외인성 또는 내인성 거대 분자를 분해하는 것이며 모든 자가포식 경로는 어느 정도 리소좀을 포함합니다(Ichimiya et al., 2020). ATPase 양이온 수송 13A2(ATP13A2) 단백질은 리소좀과 오토파지를 포함한 일부 세포 산성 소포에 국한되어 있으며, 주로 리소좀 유사 소포에서 양이온 수송을 담당합니다. ATP13A2 돌연변이는 초기 발병 PD에서 관찰될 수 있습니다(van Veen et al., 2020). 시험관 내 연구에 따르면 ATP13A2 단백질 수치가 증가하면 α-시누클레인 유발 독성이 감소하는 것으로 확인되었습니다(Murphy et al., 2013). 병원성 ATP13A2의 이형 접합 돌연변이는 ATP13A2 발현 및 미토콘드리아 기능 장애의 결함을 유발하는 것으로 알려져 있습니다. 유리 아연 이온 농도를 증가시키는 약물 치료는 미토콘드리아 단편화 및 ATP 고갈로 미토콘드리아 기능 상실을 악화시켜 세포 사멸로 이어집니다(Park et al., 2014).

OD는 PTEN 유도 추정 키나아제 1(PINK1) 유전자 매개 PD에서도 흔하지만(Ferraris et al., 2009), 미토콘드리아 손상과의 연관성은 명확하지 않습니다. 이전 연구에서는 PD와 관련된 유전자(예: Parkin RBR E3 유비퀴틴 단백질 리가제 [PRKN], PINK1) 또는 미토콘드리아 결함을 유발하는 기타 요인이 PD 발병에 기여한다고 제안했습니다(Poole et al., 2008). 미토콘드리아는 신경 세포의 높은 에너지 요구량을 충족하는 다양한 기능을 가진 중요한 세포 소기관입니다. 또한 막 전위, 세포 분화 및 세포 사멸을 조절하는 데 중요한 역할을 하며 시냅스 전 막에 활발하게 모집됩니다(Devine and Kittler, 2018). 연구에 따르면 미토콘드리아 기능 장애는 형태적 및 운동학적 변화, 에너지 생산 감소, 미토콘드리아 DNA의 변화, 활성 산소 종(ROS) 생성, 칼슘 항상성 이상을 초래할 수 있으며, 이는 PD에서 신경 세포 사멸의 근본 메커니즘으로 간주됩니다(Ammal Kaidery와 Thomas, 2018). 세포는 손상된 미토콘드리아를 선택적으로 제거하여 미토콘드리아의 품질을 관리하고 미토콘드리아 자가포식이라고 하는 자가포식 메커니즘을 촉발하여 세포를 보호합니다. 건강한 미토콘드리아 네트워크를 유지하기 위해 세포는 유사 분열을 통해 손상된 미토콘드리아를 처리하고 새로운 유효 미토콘드리아를 생성합니다(Anzell et al., 2018). 미토콘드리아 자가포식은 미토콘드리아 키나아제 PINK1과 세포질 파킨의 활성을 포함하며, 이는 PINK1/Parkin 경로를 활성화합니다(Pickrell and Youle, 2015).

PINK1의 돌연변이는 미토콘드리아 활동과 파킨 활성화를 감소시키고 유사 분열 파열로 인해 손상된 미토콘드리아가 분리되지 못하게 할 수 있습니다(Deng et al., 2008). 흥미롭게도 PINK1 돌연변이, Drp1 수준 감소, Drp1 GTPase 활성 증가 사이의 연관성은 PINK1에 의한 미토콘드리아 분열의 직접적인 유도를 시사합니다(Sandebring et al., 2009). PINK1 결핍은 또한 나트륨 이온 채널 손상과 연관되어 기존의 미토콘드리아 칼슘 항상성을 제어할 수 없는 것으로 나타났습니다(Gandhi et al., 2009). 한편으로, PINK1 기능 장애는 Mfn2 단백질 발현을 억제하여 신경 독소에 대한 DA 신경 세포의 민감도를 증가시킵니다 (Peng et al., 2019). 한편, 파킨 매개 Mfn2 유비퀴틴화는 미토콘드리아 에너지 대사와 칼슘 항상성에 필수적인 소포체-미토콘드리아 접촉의 형성에 중요한 역할을 합니다(McLelland et al., 2018). 특히, 파킨은 미토콘드리아에 우선적으로 결합하여 산화 스트레스로부터 미토콘드리아 DNA를 보호하고 미토콘드리아 DNA 복구를 촉진합니다(Rothfuss et al., 2009). 이와 대조적으로, 파킨 녹아웃 마우스 균주는 중뇌의 복부에 뉴런을 보여 심각한 미토콘드리아 손상과 복합체 I 및 IV의 감소를 나타내며 PD의 특징적인 운동 결손을 나타내지 않았습니다(Palacino et al., 2004; Stichel et al., 2007).

미토콘드리아 자가포식 경로의 결함, 특히 PARK2(PRKN 돌연변이) 및 PARK6(PINK1 돌연변이)는 가족성 PD의 주요 원인으로 생각됩니다(Wang et al., 2022). 정상적인 조건에서 미토콘드리아에 국한된 PINK1은 내부 미토콘드리아 막으로 전위되어 분해됩니다(Wang et al., 2020). 그러나 지금까지 알려지지 않은 일부 조건의 영향으로 미토콘드리아가 기능 장애를 일으켜 막 전위가 손실됩니다. 손상된 미토콘드리아는 다른 미토콘드리아 막 단백질에 작용하면서 PINK1과 PRKN의 흡수를 활성화하여 오토파지를 유도하는 데 도움을 줍니다(Heo et al., 2015). 파킨은 손상된 미토콘드리아의 프로테아좀 분해에 관여하며, 그 돌연변이는 상염색체 열성 형태의 PD를 유발할 수 있습니다(Gandhi et al., 2009). 또한 PRKN 결핍은 생쥐에서 DA 뉴런의 퇴화를 초래하고, PINK1 결핍은 생쥐 배아 섬유아세포에서 리소좀 기능 장애를 유발합니다(Demers-Lamarche et al., 2016). 정상 상태에서는 손상되거나 기능이 결핍된 미토콘드리아가 주변을 둘러싸고 단백질 분해됩니다. 그러나 파킨슨병이 진행되는 동안 PINK1과 파킨의 돌연변이는 손상된 세포 소기관의 제거를 현저히 감소시킵니다. 손상된 세포 소기관의 축적은 세포 사멸의 궁극적인 원인일 가능성이 높습니다(Anzell et al., 2018).

나이가 증가하거나 병리학적인 요인이 유도되면 미세아교세포의 미토콘드리아 DNA가 손상되고 세포 내부에 ROS가 나타납니다(von Bernhardi et al., 2015). ROS 축적은 주로 PD의 초기 단계에서 발생하며 많은 신호 경로에서 발생하며 과도한 축적은 세포 사멸을 유발하거나 가속화합니다(Morris et al., 2018). ROS에 대한 연구는 주로 SN-선조체 경로에서 DA 방출과 대사 과정에 초점을 맞춰 왔으며, OB의 DA는 여전히 연구가 필요합니다. 산화적 인산화 과정에서 복합체 I은 니코틴아미드 아데닌 디뉴클레오티드(NADH)에서 전자 수송 사슬의 하위 단위로 전자를 전달하는 촉매 역할을 하며 미토콘드리아에서 ROS 생성의 주요 부위로 간주됩니다(Wu et al., 2019). 미토콘드리아 복합체 I에서 낮은 ATP 생성 또는 기질의 높은 NADH/니코틴아마이드 아데닌 디뉴클레오티드(NAD+) 비율로 인한 높은 양성자 운동성은 다량의 과산화 라디칼을 생성하는 경향이 있습니다(그림 2). 슈퍼옥사이드 디스뮤타제 2는 슈퍼옥사이드 라디칼을 과산화수소로 전환하고, 이 과산화수소는 퍼옥시다아제에 의해 추가로 해독됩니다. 그러나 금속 이온(Fe2+)이 존재하면 과산화수소는 펜톤 반응을 거쳐 반응성이 높은 하이드록실 라디칼로 전환되어 심각한 세포 산화 손상을 일으킵니다(Murphy, 2009).

Figure 2

Mitochondrial division and the process of ROS production.

Activated Drp1 localizes to the mitochondrial membrane and interacts with the Drp1 receptor and Fis1 to form a fission complex that induces mitochondrial division. During electron transfer, molecular oxygen is formed as a superoxide by the action of complexes I and III, which is then enzymatically cleaved by SOD1 and SOD2 to form hydrogen peroxide. Hydrogen peroxide is broken down to water by a series of enzymes. However, in the presence of mitochondrial dysfunction or Fe2+, the intermediate products react with NO or form highly reactive hydroxyl radicals. Created with Microsoft PowerPoint 2021.

미토콘드리아 분열과 ROS 생성 과정.
활성화된 Drp1은 미토콘드리아 막에 국한되어 Drp1 수용체 및 Fis1과 상호 작용하여 미토콘드리아 분열을 유도하는 핵분열 복합체를 형성합니다. 전자가 이동하는 동안 분자 산소는 복합체 I과 III의 작용에 의해 슈퍼옥사이드로 형성되고, 이 슈퍼옥사이드는 SOD1과 SOD2에 의해 효소적으로 절단되어 과산화수소를 형성합니다. 과산화수소는 일련의 효소에 의해 물로 분해됩니다. 그러나 미토콘드리아 기능 장애 또는 Fe2+가 존재하면 중간 생성물이 NO와 반응하거나 반응성이 높은 하이드록실 라디칼을 형성합니다. Microsoft PowerPoint 2021으로 제작되었습니다.

ADP: Adenosine diphosphate; ATP: adenosine triphosphate; CAT: catalase; CoQ: coenzyme Q; Cyt C: cytochrome C; Drp1: dynamin-related protein 1; FADH: flavin adenine dinucleotide; Fe2+: metal ions; Fis1: mitochondrial fission protein 1; GPx: glutathione peroxidase; H2O2: hydrogen peroxide; NAD+: Nicotinamide adenine dinucleotide; NADH: nicotinamide adenine dinucleotide; NO: nitric oxide; O2: oxygen; O2•–: superoxide anion; OH•: hydroxyl radical; ONOO•: peroxynitrite; ROS: reactive oxygen species; SOD: superoxide dismutase; TPx; thioredoxin reductase.

DA is metabolized through oxidative deamination catalyzed by monoamine oxidase, a process that produces hydrogen peroxide that can be scavenged by antioxidant systems (Yeung et al., 2019). In the SN, alterations in DA, iron, and α-synuclein selectively contribute to oxidative stress. Ferritin tightly maintains a cytoplasmically unstable iron pool for ferritin functions, including tyrosine hydroxylase-mediated production of DA (Hare and Double, 2016). α-Synuclein can promote synaptic DA release and repackaging, including the DA reuptake processes mediated by DAT proteins (Runwal and Edwards, 2021). In PD, oxidation and phosphorylation of α-synuclein disrupt the transferrin receptor-mediated iron import process and require the involvement of divalent metal transporter protein 1, which is not regulated by intracellular iron levels (Hare and Double, 2016; Zeng et al., 2021).

During oxidative stress, DA undergoes oxidative metabolism through multiple pathways, generating large amounts of hydrogen peroxide and superoxide anions, which are catalyzed by divalent iron at the SN to produce more toxic hydroxyl radicals (Singh et al., 2019). Dopaminergic neurons are sensitive to mitochondrial ROS (Kim et al., 2011). When the complex I activity of nigrostriatal mitochondria decreases during this process, glutathione-based antioxidants disappear and free radicals cannot be scavenged (Puspita et al., 2017). For example, some toxin compounds, including rotenone, are free to cross biofilms and accumulate in mitochondria after ingestion, reducing NADH dehydrogenase activity and blocking the electron transfer process (Trist et al., 2019). In turn, free radicals impair membrane function of DA neurons or directly damage cellular DNA, leading to neuronal degeneration (Dan et al., 2021). Mitochondrial damage promotes the accumulation of oxidized DA and the reduction of glucocerebrosidase (Ysselstein et al., 2019), which also suggests that DA is the bridge between α-synuclein accumulation and lysosomal damage.

Since many previous studies have highlighted the critical role of autophagic degradation in aberrant accumulation of α-synuclein and neurodegeneration in PD, members of the autophagic pathway have great potential to be investigated for early detection or blockade of PD (Arotcarena et al., 2019; Parekh et al., 2019; Navarro-Romero et al., 2020). A fundamental question to consider is whether stimulation of autophagy has a protective effect against PD. Excessive activation of the autophagic pathway may be neurotoxic, and lysosomal clearance can be stressful to cells. At this stage, the choice of therapeutic agents is still limited since studies on the molecular mechanisms underlying the pathological process of PD are still in the exploratory stage and a greater emphasis has been placed on early onset and blockade. Although some of the mechanisms associated with the onset of PD have been enumerated or the same signaling pathways have been suggested to trigger different forms of pathology, finding drugs that can improve PD symptoms can be difficult.

DA는 모노아민 산화효소에 의해 촉매되는 산화 탈아민화를 통해 대사되며, 이 과정에서 항산화 시스템에 의해 제거될 수 있는 과산화수소가 생성됩니다(Yeung et al., 2019). SN에서 DA, 철, α-시누클레인의 변화는 산화 스트레스에 선택적으로 기여합니다. 페리틴은 티로신 하이드 록 실라 제 매개 DA 생산을 포함하여 페리틴 기능을 위해 세포질 적으로 불안정한 철 풀을 단단히 유지합니다 (Hare and Double, 2016). α-시누클레인은 DAT 단백질에 의해 매개되는 DA 재흡수 과정을 포함하여 시냅스 DA 방출 및 재포장을 촉진할 수 있습니다(Runwal and Edwards, 2021). PD에서 α-시누클레인의 산화 및 인산화는 트랜스페린 수용체 매개 철 수입 과정을 방해하고 세포 내 철 수준에 의해 조절되지 않는 2가 금속 수송 단백질 1의 개입을 필요로 합니다(Hare and Double, 2016; Zeng et al., 2021).

산화 스트레스 동안 DA는 여러 경로를 통해 산화 대사를 거쳐 다량의 과산화수소와 슈퍼옥사이드 음이온을 생성하며, 이는 SN에서 2가 철에 의해 촉매되어 더 많은 독성 하이드 록실 라디칼을 생성합니다 (Singh et al., 2019). 도파민성 뉴런은 미토콘드리아 ROS에 민감합니다(Kim et al., 2011). 이 과정에서 니그로스트리아 미토콘드리아의 복합체 I 활성이 감소하면 글루타치온 기반 항산화 물질이 사라지고 자유 라디칼을 제거 할 수 없습니다 (Puspita et al., 2017). 예를 들어, 로테논을 포함한 일부 독소 화합물은 섭취 후 자유롭게 바이오필름을 통과하여 미토콘드리아에 축적되어 NADH 탈수소효소 활성을 감소시키고 전자 전달 과정을 차단합니다(Trist et al., 2019). 결과적으로 자유 라디칼은 DA 뉴런의 막 기능을 손상시키거나 세포 DNA를 직접 손상시켜 뉴런의 퇴화를 초래합니다(Dan et al., 2021). 미토콘드리아 손상은 산화된 DA의 축적과 글루코세레브로시다아제의 감소를 촉진하며(Ysselstein 등, 2019), 이는 또한 DA가 α-시누클린 축적과 리소좀 손상 사이의 다리 역할을 한다는 것을 시사합니다.

이전의 많은 연구에서 PD에서 α-시누클린의 비정상적인 축적과 신경 퇴행에서 자가포식 분해의 중요한 역할이 강조되었으므로, 자가포식 경로의 구성원은 PD의 조기 발견 또는 차단을 위해 조사될 가능성이 매우 높습니다(Arotcarena 외, 2019; Parekh 외, 2019; Navarro-Romero 외, 2020). 고려해야 할 근본적인 질문은 오토파지의 자극이 PD에 대한 보호 효과가 있는지 여부입니다. 자가포식 경로의 과도한 활성화는 신경 독성을 유발할 수 있으며, 리소좀 제거는 세포에 스트레스를 줄 수 있습니다. 현 단계에서는 PD의 병리학적 과정의 기초가 되는 분자 메커니즘에 대한 연구가 아직 탐색 단계에 있고 조기 발병과 차단에 더 중점을 두고 있기 때문에 치료제의 선택은 여전히 제한적입니다. PD 발병과 관련된 일부 메커니즘이 열거되었거나 동일한 신호 경로가 다른 형태의 병리를 유발하는 것으로 제안되었지만, PD 증상을 개선할 수 있는 약물을 찾는 것은 어려울 수 있습니다.

Available drugs to improve the motor and non-motor symptoms of PD and their therapeutic effects

Treatment of PD focuses on improving motor and non-motor symptoms, and the medications currently used are primarily designed to slow the progression of PD. DA-based pharmacotherapy usually contributes to initial improvement in motor symptoms, while continued medication also tends to lead to prolonged drug withdrawal. Non-motor symptoms are treated with non-dopaminergic approaches, such as selective 5-HT reuptake inhibitors for psychiatric symptoms (Armstrong and Okun, 2020). Dopaminergic treatment does not affect olfactory deficits in the early stages of PD, and commonly used antidepressants may not be effective in treating depressive symptoms of PD (Bang et al., 2021). Therefore, improving the non-motor symptoms of PD is challenging. Table 1 summarizes the improvement of PD symptoms by drugs modulating their respective target genes.

파킨슨병의 운동 및 비운동 증상 개선을 위해 사용 가능한 약물과 그 치료 효과

파킨슨병의 치료는 운동 및 비운동 증상 개선에 중점을 두며, 현재 사용되는 약물은 주로 파킨슨병의 진행을 늦추기 위해 고안되었습니다. DA 기반 약물 요법은 일반적으로 운동 증상의 초기 개선에 기여하지만, 약물을 계속 복용하면 약물 금단 증상이 장기화되는 경향이 있습니다. 비운동 증상은 정신과적 증상에 대한 선택적 5-HT 재흡수 억제제와 같은 비도파민성 접근법으로 치료합니다(암스트롱과 오쿤, 2020). 도파민성 치료는 PD 초기 단계의 후각 결손에는 영향을 미치지 않으며, 일반적으로 사용되는 항우울제는 PD의 우울 증상을 치료하는 데 효과적이지 않을 수 있습니다(Bang et al., 2021). 따라서 파킨슨병의 비운동 증상을 개선하는 것은 어려운 과제입니다. 표 1은 각각의 표적 유전자를 조절하는 약물에 의한 파킨슨병 증상 개선 효과를 요약한 것입니다.

Table 1

PD drug therapy with corresponding targets

Target of actionModelCell modelDrugEfficacy eval‎uationReference

TLR4/NF-κB	–	LPS-induced cell (RAW264.7 macrophages, 1 μg/mL)	Aloperine (50 and 100 μM)	TNF-α↓ IL-6 ↓ IL-17A ↓ NO ↓ PGE2 ↓ TLR4/NF-κB↓	Ye et al., 2020
BDNF/Nrf2/NF-κB	6-OHDA-induced C57BL/6J mice	–	Schisandra chinensis	ROS reduction BDNF↑ Nrf2↑ GSK-3β ↓ caspase 3 ↓ caspase 9↓	Yan et al., 2021
BDNF/TrkB/CREB	Rotenone-induced C57BL/6J mice (2.5 mg/kg,	–	Baicalein	α-syn ↓ inflammatory response↓	Zhao et al., 2021
	2-week injection)		(4-wk treatment, 300 mg/kg/d)	CREB↑ PI3K/Akt↑ CaMK II↑ BDNF/TrkB↑
NF-κB	LPS-induced C57BL/6J mice	–	Ginsenoside Rg1 (10, 20, 40 mg/kg/d), 18 d	Proinflammatory cytokines↑ Anti-inflammatory cytokines ↓ NF-κB↓	Liu et al., 2020
TLR/NF-κB	MPTP-induced Sprague–Dawley mice	LPS-induced PC12 cell	Cordycepin	Mitigation of motor impairment and DA neuron loss TLR/NF-κB↓	Cheng and Zhu, 2019
TLR/NF-κB/MAPK	MPTP-induced C57BL/6J mice	LPS-induced BV2 cell	Calycosin	Reduced behavioral disturbances and inflammatory response TLR/NF-κB ↓ MAPK↓	Yang et al., 2019
MEF2D-ND6	MPTP-induced C57BL/6J mice	MPP+-induced SN4741 cell	Salidroside	Preservation of mitochondrial morphology and function MEF2D-ND6↓	Li et al., 2020
MALAT1/miR-129/SNCA	MPTP-induced mice (20 mg/kg)	–	Resveratrol (50 mg/kg)	TH+ cell↑ miR-129↑ MALAT1 ↓ SNCA↓	Xia et al., 2019
NLRP3/Caspase-1/ IL-1β	MPTP-induced mice (30 mg/kg)	MPP+-induced cell (SH-SY5Y)	Echinacoside (40 mg/kg)	TH↑ NLRP3 ↓ caspase 1 ↓ IL-1β↓	Gao et al., 2020
PINK1/Parkin	C. elegans	6-OHDA-induced SH-SY5Y cell	Maackiain	Blocking apoptosis Ubiquitin-proteasome system↑ PINK1/Parkin↑	Tsai et al., 2020
SNCA	MPTP-induced C57BL/6J mice (25 mg/kg)	–	Ginsenoside Rg1 (10, 20, 40 mg/kg/d), 52 d	Inhibits the activation of microglia and astrocytes TNF-α ↓ IL-1β ↓ p-α-syn↓	Heng et al., 2016
SNCA/P2RX4	C57BL/6J mice Thy 1-SNCA transgenic mice	SK-N-SH cells	Piperine (25, 50, 100 mg/kg), 6 wk	Activate P2RX4 α-syn ↓ STX1 ↓ Relieve olfactory dysfunction	Li et al., 2022
SNCA/AMPK-mTOR-TFEB	hA53T α-syn transgenic mice	N2a cells	Harmol (10, 20, 40 mg/kg), 1 mon	α-syn ↓ Phosphorylation of AMPK ↓ Phosphorylation of mTOR ↓ TFEB↑	Xu et al., 2022b
SNCA/GSK-3β	MPTP-induced C57BL/6J mice (20 mg/kg)	SH-SY5Y cells	6-Bio	Enhance autophagy Inhibit GSK-3β α-syn↓	Suresh et al., 2017

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“–” represents that no animal or cell studies have been carried out in this paper. 6-Bio: A small molecule autophagy modulator; 6-OHDA: 6-hydroxydopamine; AMPK: adenosine 5′-monophosphate; BDNF: brain-derived neurotrophic factor; CaMK II: calcium/calmodulin-dependent protein kinase type II; CREB: cyclic-adenosine monophosphate response binding protein; DA: dopamine; GSK-3β: glycogen synthase kinase-3β; IL: interleukin; LPS: lipopolysaccharide; MALAT1: metastasis-associated lung adenocarcinoma transcript 1; MAPK: mitogen-activated protein kinase; MEF2D: myocyte enhancer factor 2D; miR: microRNA; MPP+: 1-methyl-4-phenylpyridinium; MPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin; mTOR: mammalian target of rapamycin; ND6: NADH dehydrogenase 6; NF-κB: nuclear factor-κB; NLRP3: NOD-, LRR- and pyrin domain-containing protein 3; NO: nitrogen monoxide; Nrf2: nuclear factor erythroid 2-related factor 2; P2RX4: purinergic receptor P2X 4; PGE2: prostaglandin E2; PI3K: phosphoinositide 3-kinase; PINK1: PTEN-induced putative kinase 1; p-α-syn: phosphorylated α-synuclein; ROS: reactive oxygen species; TFEB: transcription factor EB; TH: tyrosine hydroxylase; TLR: Toll-like receptor; TNF-α: tumor necrosis factor-α; α-syn: α-synuclein.

As shown in Table 1, some herbal medicines exhibit neuroprotective effects in the treatment of brain-related diseases; therefore, exploration of the corresponding targets and their signaling pathways may offer great potential for the treatment of neurodegenerative diseases such as PD. The mechanisms of target genes that predispose patients to PD-like symptoms and the occurrence of olfactory disorders deserve in-depth study. Similarly, targeting phosphorylated α-synuclein and reducing its increase with pathological progression is a promising therapeutic strategy. In one study, targeted metal ion compounds were developed to positively modulate α-synuclein metal junctions and accumulation (Finkelstein et al., 2017). Among the phosphorylation-related pathologies of α-synuclein, the process of autophagy induced by potent inducers plays a dominant role, thereby reducing the abnormal accumulation of α-synuclein.

Olfactory dysfunction as an early biomarker of neurodegenerative disease

OD is a common symptom of several diseases such as neurodegenerative disorders, psychiatric disorders, and coronavirus disease 2019 (COVID-19) (Doty, 2012; Hasegawa et al., 2022), causing clinical difficulties in directly determining disease on this basis. Clinical and experimental evidence suggests that pathological changes in the OB, such as the formation of pathological protein aggregates and changes in neurotransmitter signaling, occur early in the development of PD (Rey et al., 2018). OD is associated with disease progression and cognitive decline in PD. Studies on the molecular mechanisms and interactions in the olfactory process can contribute to the refinement of the pathological framework of PD and delay subsequent motor symptoms.

The discovery of OR proteins, which act as a physical barrier between the environment and the brain, has changed the direction of research on the mechanisms of olfaction. Understanding the diversity and specificity of ORs is a prerequisite for understanding the molecular basis of olfaction (Breer, 2003). Both in vitro and in vivo functional studies have confirmed the chemosensory role of ORs. ORs are reactivated by different compounds that instruct olfactory sensory neuron regulation, confer selective odor responses to olfactory sensory neurons, and respond differently to the same odorant (Floriano et al., 2004; Shirokova et al., 2005; Abaffy et al., 2006). Modern olfactory stimulation theory revolves around the presence of various active enzymes in the olfactory epithelium. Odor selectively inhibits the function of these enzymes, altering the relative concentrations of certain compounds in the receptor and resulting in nerve impulses (Wendt, 1952).

Various studies have highlighted the role of G protein-coupled, cAMP-mediated transduction mechanisms in odor recognition and discrimination (Pace et al., 1985; Sklar et al., 1986; Kajiya et al., 2001). OR proteins increase the local concentration of cAMP and Ca2+ through CNG channels and also direct the centralized location of axons in the OB. Another mechanism of regulation of Ca2+ concentration is fixation from the nucleus through the guanine nucleotide exchange factor. An increase in Ca2+ concentration is accompanied by an increase in the concentration of nitric oxide synthase, which produces nitric oxide. Nitric oxide activates soluble guanylate cyclase via cAMP and locally produces cGMP, which affects axonal guidance and regulates axonal gene expression‎ at the local and nuclear levels (Sharma et al., 2019). At present, due to the pre-eminence of non-motor symptoms in the pathological process and the low harm to patients from testing olfactory function, studies on the common signaling pathways of olfactory impairment and PD can be considered, and signaling factors, including Ca2+, can be used as a breakthrough.

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Conclusions and Future Perspectives

The use of OD as a clinical biomarker for neurodegenerative diseases can contribute to the prodromal characterization of these diseases, early diagnostic strategies, and the feasibility of differential diagnosis and subsequent treatment. In olfactory function testing, the primary and most challenging task is to reduce the influence of complex factors that can cause hypofunction, explore the relationship between a single variable and OD in PD patients, and elaborate on the lesion areas closely related to the variable. The complexity and high connectivity of the neural network of the olfactory system can facilitate the diffusion of pathogenic factors to other functional areas of the brain through secondary olfactory structures such as the OB, which may induce changes in the levels of neurotransmitters and thus affect the abnormal accumulation of α-synuclein in the olfactory pathway. The rhythm of neurotransmitter release from synaptic structures is then further affected by α-synuclein, which may lead to an irreversible pathological process.

Depending on the developmental process, α-synuclein levels can be reduced by decreasing synthesis and accumulation and increasing degradation. Specific feasible measures and promising targeted drugs for each process are currently being investigated and are expected to yield effective therapeutic strategies to delay or stop pathological progression in the early stages of PD. Studies have also shown a strong emphasis on the molecular-level pathological mechanisms of PD, exploring the feedback relationships between various target genes and cytokines in the development of mitochondrial-lysosomal autophagy, oxidative stress and inflammatory responses, as well as the targets for drug delivery. Studies on the possible mechanisms of OD can be combined to search for effective targets and signaling factors that overlap between the two and either inhibit or enhance to achieve the effect of slowing down the pathological process of PD. Although target delivery drugs to enhance autophagy are being explored, the blocking effect of the blood-brain barrier cannot be ignored, and practical factors such as advanced patient age also need attention. Therefore, additional research is required to explore the specific contributions of optimal delivery modalities to the mechanism of OD and to study the tracking of drug targets and metabolic processes in vivo to alleviate the continuous deterioration of pathology in the early stage of PD.

결론 및 향후 전망

신경 퇴행성 질환의 임상 바이오마커로 후각 기능을 사용하면 

이러한 질환의 전구 특성, 조기 진단 전략, 감별 진단 및 후속 치료의 실현 가능성에 기여할 수 있습니다. 

후각 기능 검사에서 가장 중요하고 어려운 과제는 

기능 저하를 유발할 수 있는 복잡한 요인의 영향을 줄이고, 

PD 환자에서 단일 변수와 OD 사이의 관계를 탐색하며, 

변수와 밀접하게 관련된 병변 영역을 정교하게 분석하는 것입니다. 

후각 시스템의 신경 네트워크의 복잡성과 높은 연결성은 병원성 인자가 OB와 같은 이차 후각 구조를 통해 뇌의 다른 기능 영역으로 확산되는 것을 촉진하여 신경 전달 물질 수준의 변화를 유도하여 후각 경로에서 α- 시누클린의 비정상적인 축적에 영향을 미칠 수 있습니다. 시냅스 구조에서 신경 전달 물질 방출의 리듬은 α- 시누클레인에 의해 더 영향을 받아 돌이킬 수없는 병리학 적 과정으로 이어질 수 있습니다.

발달 과정에 따라 합성과 축적을 줄이고 분해를 증가시킴으로써 α-시누클레인 수치를 낮출 수 있습니다. 현재 각 과정에 대한 구체적인 실현 가능한 조치와 유망한 표적 약물이 연구되고 있으며, 이를 통해 파킨슨병의 초기 단계에서 병리적 진행을 지연시키거나 중단시킬 수 있는 효과적인 치료 전략이 나올 것으로 기대됩니다. 또한 미토콘드리아-리소좀 자가포식, 산화 스트레스 및 염증 반응의 발달에서 다양한 표적 유전자와 사이토카인 간의 피드백 관계와 약물 전달 표적을 탐색하는 등 PD의 분자 수준의 병리학적 메커니즘에 대한 연구가 활발히 진행되고 있습니다. 이 두 가지가 겹치는 효과적인 표적과 신호 인자를 찾고 이를 억제하거나 강화하여 PD의 병리학적 과정을 늦추는 효과를 얻기 위해 가능한 메커니즘에 대한 연구를 결합할 수 있습니다. 자가포식을 강화하는 표적 전달 약물이 연구되고 있지만, 혈액뇌장벽의 차단 효과도 무시할 수 없고, 환자의 고령과 같은 현실적인 요인도 고려해야 합니다. 따라서 파킨슨병 초기 단계의 지속적인 병리 악화를 완화하기 위해 최적의 전달 방식이 파킨슨병의 메커니즘에 구체적으로 기여하는 바를 탐구하고 생체 내 약물 표적과 대사 과정을 추적하는 연구가 추가로 필요합니다.

Additional file: Open peer review report 1.

OPEN PEER REVIEW REPORT 1

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Footnotes

Funding: This work was supported by the National Natural Science Foundation of China, No. 82104421, the China Postdoctoral Science Foundation, No. 2022M721726, the Innovation and Entrepreneurship Training Program for College Students of Jiangsu Province, No. 202210304155Y, and the Research Startup Fund Program of Nantong University, No.135421623023 (all to XZ).

Conflicts of interest: The authors declare no competing interests.

Data availability statement: The data that support the findings of this study are available from the corresponding author upon reasonable request.

Open peer reviewer: Christian Barbato, Institute of Biochemistry and Cell Biology, National Research Council, Italy.

P-Reviewer: Barbato C; C-Editor: Zhao M; S-Editors: Yu J, Li CH; L-Editors: Yu J, Song LP; T-Editor: Jia Y

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