Re: L-serine(FDA 승인) --＞ 글리신 대사.. neuroprotection 탐구!!

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https://kr.iherb.com/pr/nutricost-l-serine-powder-unflavored-8-oz-227-g/132259

Biomedicines. 2023 Aug; 11(8): 2117.

Published online 2023 Jul 27. doi: 10.3390/biomedicines11082117

PMCID: PMC10452085

PMID: 37626614

L-serine: Neurological Implications and Therapeutic Potential

Soe Maung Maung Phone Myint and Liou Y. Sun*

Biancamaria Longoni, Academic Editor

Author information Article notes Copyright and License information PMC Disclaimer

Associated DataData Availability Statement

Abstract

L-serine is a non-essential amino acid that plays a vital role in protein synthesis, cell proliferation, development, and sphingolipid formation in the central nervous system. It exerts its effects through the activation of glycine receptors and upregulation of PPAR-γ, resulting in neurotransmitter synthesis, neuroprotection, and anti-inflammatory effects. L-serine shows potential as a protective agent in various neurological diseases and neurodegenerative disorders. Deficiency of L-serine and its downstream products has been linked to severe neurological deficits. Despite its crucial role, there is limited understanding of its mechanistic production and impact on glial and neuronal cells. Most of the focus has been on D-serine, the downstream product of L-serine, which has been implicated in a wide range of neurological diseases. However, L-serine is approved by FDA for supplemental use, while D-serine is not. Hence, it is imperative that we investigate the wider effects of L-serine, particularly in relation to the pathogenesis of several neurological deficits that, in turn, lead to diseases. This review aims to explore current knowledge surrounding L-serine and its potential as a treatment for various neurological diseases and neurodegenerative disorders.

초록

L-세린은 

중추신경계에서 

단백질 합성, 

세포 증식, 발달 및 

스핑고지질 형성에 중요한 역할을 하는 

비필수 아미노산입니다. 

L-serine is a non-essential amino acid that plays a vital role in

protein synthesis,

cell proliferation, development, and

sphingolipid formation in the central nervous system.

글리신 수용체의 활성화와 PPAR-γ의 상향 조절을 통해 

그 효과를 발휘하여 

신경전달물질 합성, 신경 보호 및 항염증 효과를 가져옵니다.

 L-세린은 

다양한 신경 질환 및 신경 퇴행성 질환에 대한 

보호제로서의 잠재력을 보여줍니다. 

L-세린과 

그 하류 생성물의 결핍은 

심각한 신경학적 결핍과 관련이 있습니다. 

L-세린의 중요한 역할에도 불구하고 

신경교세포와 신경세포에 미치는 영향과 그 메커니즘에 대한 이해는 

제한적입니다. 

대부분의 초점은 광범위한 신경 질환과 관련이 있는 

L-세린의 하류 산물인 D-세린에 맞춰져 있습니다. 

그러나 

L-세린은 보충제로 FDA의 승인을 받았지만, 

D-세린은 그렇지 않습니다.

 따라서, 

특히 질병을 유발하는 여러 신경학적 결핍의 발병 기전과 관련하여 

L-세린의 광범위한 효과를 조사하는 것이 필수적입니다. 

이 리뷰는 

다양한 신경 질환 및 신경 퇴행성 장애의 치료제로서 

L-세린에 관한 최신 지식과 그 잠재력을 탐구하는 것을 목표로 합니다.

Keywords: L-serine, Alzheimer’s disease, neuroinflammation, metabolism, D-serine, Parkinson’s disease, multiple sclerosis, brain injury

1. Serines and Their Role in the Central Nervous System

Despite being categorized as a non-essential amino acid, L-serine has repeatedly demonstrated beneficial effects by acting as a precursor to crucial molecules required for protein synthesis, cell proliferation, and development. Its role in the formation of sphingolipids in the central nervous system is essential for neural differentiation and survival [1,2]. L-serine is produced via the phosphorylated pathway in the mammalian brain and is derived from glucose from glycolysis rather than phosphenolpyruvate from gluconeogenesis [3]. However, L-serine uptake from blood across the blood-brain barrier is inefficient when compared to other essential amino acids [4].

L-serine also serves as a precursor to glycine and D-serine, which are important for excitatory glutamatergic neurotransmission. D-serine is involved in long-term potentiation and synaptic plasticity, while glycine acts on extra-synaptic NMDARs [5,6]. L-serine is produced primarily in glial cells, specifically astrocytes, and is converted to D-serine via the enzyme serine racemase [7].

While D-serine can cause NMDA-mediated excitotoxicity, L-serine has been found to exert neuroprotective effects by mitigating neurotoxicity through the activation of the glycine receptor and increasing the expression‎ of PPAR-y, which plays a crucial role in macrophage and microglia polarization [8,9,10,11,12]. Following a neurological disease, glial cells are activated and contribute to the inflammatory response [13,14]. Microglial cells can shift to certain phenotypes, with the M1 phenotype producing reactive oxygen species that can initiate cell death while the M2 phenotype allows for repair through phagocytosis and anti-inflammatory factor production [15,16].

L-serine plays a role in the polarization of macrophages to certain phenotypes and has anti-inflammatory effects through the downregulation of microglia and astrocyte proliferation and activation [10,17]. It reduces the production of proinflammatory cytokines and serves as a protective agent, particularly after injury. A recent study has suggested that neuroinflammation that appears as a result of traumatic brain injury at high altitude is ameliorated by L-serine, likely due to the mechanism of microglial polarization reducing neuroinflammation in the process [18]. All in all, L-serine in addition to serving as a protective agent, can even reverse the increase in volume of brain lesions and contributes to the healing process of brain tissue [18].

1. 세린과 중추신경계에서의 역할

L-세린은

비필수 아미노산으로 분류되지만

단백질 합성, 세포 증식 및 발달에 필요한

중요한 분자의 전구체 역할을 함으로써

유익한 효과가 반복적으로 입증되었습니다.

중추신경계에서

스핑고지질 형성에 관여하는 L-세린의 역할은

신경 분화와 생존에 필수적입니다[1,2].

생리활성 스핑고지질은 스핑고신, 세라마이드, 스핑고신-1-포스페이트(S1P) 및 세라마이드-1-포스페이트를 포함한 지질 군을 구성합니다. 이러한 분자들은 키나아제, 포스파타제, 리파아제 및 기타 효소와 막 수용체를 포함한 고유한 단백질 표적에 작용하며 고유한 세포 기능을 발휘합니다.스핑고지질의 세계인 스핑고리포좀은 각 생리활성 지질의 분자 종과 하나의 생리활성 지질을 다른 생리활성 지질로 전환하는 대사 상호 연결(예: 세라마이드에서 스핑고신, 그리고 S1P로 전환)이 매우 복잡하게 얽혀 있습니다. 중요한 것은 이러한 경로가 스핑고지질의 특정 기능을 지시하는 것으로 보이는 특정 세포 내 국소화를 보여준다는 점입니다.성장 조절, 세포 이동, 접착, 세포 사멸, 노화 및 염증 반응을 포함하여 수많은 세포 생물학적 과정이 생리활성 스핑고지질에 의해 결정적으로 조절됩니다.조직 및 유기체 수준에서 생리활성 스핑고지질은 신경 퇴행성 과정, 대사 장애, 다양한 암(및 다양한 암 특성), 면역 기능, 심혈관 질환 및 피부 무결성과 관련이 있는 것으로 밝혀졌습니다.스핑고지질 대사의 효소, 그 메커니즘 및 구조를 규명하는 데 큰 진전이 있었습니다. 그러나 이러한 효소와 그 생성물이 구체적으로 조절되는 생화학적 메커니즘을 해독하는 것이 주요 과제입니다.향후 주요 과제는 특정 종 또는 생리활성 스핑고지질의 하위 그룹(예: 고유 세라마이드 및 고유 스핑고이드 염기)에 대한 분자 작용 메커니즘을 규명하는 것입니다. 초록 지난 몇 년 동안 생리활성 지질과 특히 스핑고지질에 대한 연구가 활발해지면서 게놈이나 프로테옴에 버금가는, 아니 그 이상의 복잡성을 지닌 리피돔과 그 다양한 기능이 전례 없이 밝혀지고 있습니다. 이러한 결과는 모든 주요 세포 신호 경로를 포함한 대부분의 주요 세포 생물학적 반응에서 생리활성 스핑고지질의 중요한 역할을 강조하며, 스핑고지질 대사를 주요 인간 질병과 연관시킵니다. 그럼에도 불구하고 아직 초기 단계인 생리활성 스핑고지질 분야는 경로 및 효소 조절의 분자 메커니즘 정의, 지질-단백질 상호작용 연구, 세포 프로브, 적절한 바이오마커 및 치료 접근법 개발 등 생화학적 및 분자적 기반에 대한 도전에 직면해 있습니다.

L-세린은

포유류의 뇌에서 인산화 경로를 통해 생성되며

포도당 생성을 통한 포스페놀피루베이트가 아닌

해당 작용을 통한 포도당에서 파생됩니다 [3].

그러나

혈액-뇌 장벽을 통해 혈액에서

L-세린을 흡수하는 것은 다른 필수 아미노산에 비해 비효율적입니다[4].

L-세린은

또한 흥분성 글루탐산 신경전달에 중요한

글리신과 D-세린의 전구체 역할도 합니다.

D-세린은

장기 강화 및 시냅스 가소성에 관여하는 반면,

글리신은 시냅스 외 NMDAR에 작용합니다[5,6].

L-세린은

주로 신경교세포,

특히 성상교세포에서 생성되며,

효소 세린 라세마제를 통해 D-세린으로 전환됩니다 [7].

D-세린은

NMDA 매개 흥분 독성을 유발할 수 있는 반면,

L-세린은 글리신 수용체의 활성화를 통해 신경 독성을 완화하고

대식세포와 미세아교세포 분극에 중요한 역할을 하는

PPAR-y의 발현을 증가시켜

신경 보호 효과를 발휘하는 것으로 밝혀졌습니다 [8,9,10,11,12].

신경 질환이 발생하면

신경교세포가 활성화되어

염증 반응에 기여합니다 [13,14].

미세아교세포는

특정 표현형으로 전환될 수 있으며,

M1 표현형은 세포 사멸을 유발할 수 있는 활성 산소종을 생성하는 반면

M2 표현형은 식균 작용과 항염증 인자 생성을 통해 회복할 수 있습니다[15,16].

L-세린은

대식세포를 특정 표현형으로 양극화시키는 역할을 하며

미세아교세포와 성상세포 증식 및 활성화의 하향 조절을 통해

항염증 효과를 나타냅니다 [10,17].

특히 부상 후 전 염증성 사이토카인의 생성을 감소시키고 보호 작용을 합니다.

최근 연구에 따르면

높은 고도에서 외상성 뇌 손상의 결과로 나타나는 신경염증은

L-세린에 의해 개선되며,

그 과정에서 미세아교세포 분극이

신경염증을 감소시키는 메커니즘 때문일 가능성이 높다고 합니다 [18].

대체로

L- 세린은 보호제 역할을 할뿐만 아니라

뇌 병변의 부피 증가를 역전시킬 수 있으며

뇌 조직의 치유 과정에 기여할 수 있습니다 [18].

2. Serines and Their Role in Metabolism

The acquisition of serine by our cells follow along four major pathways: through the extracellular environment, from cellular proteins that have degraded, from glycine transamination and from glucose and glutamate de novo [19]. As previously mentioned, serines are crucial in the growth and proliferation of our cells, produced mainly by the de novo synthesis of serine [20]. An important molecule that contributes and coordinates the way in which nutrients and growth factors are available for cells to grow, divide and differentiate is mammalian target of rapamycin (mTOR), a serine-threonine kinase [21]. mTOR upregulates certain key enzymes to promote the synthesis and metabolism of serine [22] and partakes in functions that support innate and adaptive immune responses [23]. mTOR enhances glycolysis and enable the differentiation, proliferation of effector T cells [24] and mTORC1 exhibits increased activity during the pro- and pre-B stages during the developmental stages of mouse B cells [21]. In terms of innate immunity, serine metabolism through mTOR contributes directly to the growth and proliferation of many innate immune cell. Specifically, mTORC1 appears to be activated and is crucial when producing IFN-γ, a key cytokine produced by NK cells [25]. Research has shown how the restriction of rate of glycolysis tends to directly also restricts the production of IFN-γ [25]. Additionally, in neutrophils mTOR is stimulated by IL-23 and the inhibition of the mTOR pathway tends to have effects that in turn reduces the production of IL-17 and IL-22 induced by IL-23 [26]. Taken altogether, we can see how serine is implicated in metabolism, particularly in relation to the immune system through the mTOR signaling pathway. Serines and the role they play in the central nervous system, metabolism, and the production of serines via the phosphorylated pathway are depicted in Figure 1.

2. 세린과 신진대사에서 세린의 역할

세포가 세린을 획득하는 경로는

세포 외 환경,

분해된 세포 단백질,

글리신 트랜스아미네이션,

포도당 및 글루타메이트 신규 합성 [19]의

네 가지 주요 경로를 따릅니다.

앞서 언급했듯이

세린은 세포의 성장과 증식에 중요한 역할을 하며,

주로 세린의 신규 합성에 의해 생성됩니다 [20].

세포가 성장, 분열 및 분화할 수 있도록

영양분과 성장 인자를 제공하는 데 기여하고 조정하는 중요한 분자는

세린-트레오닌 키나아제인 포유류 라파마이신 타겟(mTOR)입니다[21].

mTOR는

특정 주요 효소를 상향 조절하여

세린의 합성과 대사를 촉진하고[22]

선천성 및 적응성 면역 반응을 지원하는 기능에 참여합니다[23].

mTOR는 해당 작용을 강화하고

이펙터 T 세포의 분화,

증식을 가능하게 하며[24],

mTORC1은 마우스 B 세포의 발달 단계 중 전구 및 전-B 단계에서 증가된 활성을 보입니다[21].

선천성 면역의 측면에서

mTOR을 통한 세린 대사는

많은 선천성 면역 세포의 성장과 증식에 직접적으로 기여합니다.

특히,

mTORC1은 활성화된 것으로 보이며

NK 세포에서 생성되는 주요 사이토카인인

IFN-γ를 생성할 때 중요한 역할을 합니다 [25].

연구에 따르면 해당 과정의 속도를 제한하면 IFN-γ의 생산도 직접적으로 제한되는 경향이 있습니다 [25]. 또한 호중구에서 mTOR는 IL-23에 의해 자극되며, mTOR 경로를 억제하면 IL-23에 의해 유도된 IL-17 및 IL-22의 생성을 감소시키는 효과가 있는 경향이 있습니다 [26]. 이를 종합하면 세린이 신진대사, 특히 면역 체계와 관련하여 mTOR 신호 전달 경로를 통해 어떻게 관여하는지 알 수 있습니다. 세린과 세린이 중추 신경계, 신진대사 및 인산화 경로를 통한 세린 생성에서 수행하는 역할은 그림 1에 나와 있습니다.

3. Serines and Parkinson’s Disease (PD)

L-serine because of its neuroprotective properties have been utilized in a myriad of ways to treat a vast array of neurological diseases ranging from epilepsy to Alzheimer’s Disease (AD) [27,28]. L-serine treatment has been shown to improve behavior, EEG and seizure frequency in the variants that no longer possess or overexpress the NMDAR [29]. One of the earliest studies (1993) that provided a comparison of the levels of D-serine in the human temporal cortex in the normal, Alzheimer and Parkinson’s models have shown to have no significant differences [30]. However, subsequent studies have shown the efficacy of using D-serine to target Parkinson’s disease and therefore implicating the role D-serine plays in Parkinson’s. A study in 2011 showed that D-serine and Serine Racemase are both found in the astrocytes and tyrosine hydroxylase positive neurons of the substantia nigra [31]. Because of the indication that D-Ser and SR are localized in those specific areas, it is surmised that D-serine might also be present in the Parkinson’s Disease implicated areas and hence by extension causing them to believe that the levels of D-ser and SR maybe somewhat affected during the development of Parkinson’s in the mouse model (MPTP/p) [31]. In the study after the induction of PD through the administration of MPTP for 5 weeks, despite the number of TH+ neurons being reduced dramatically, the levels of D-ser and SR were lower and not observed in the TH+ neurons of the substantia nigra but the levels of D-Ser and SR were higher in both astrocytes and nondopaminergic neurons in the striatum [31].

Another study in 2019 also found that D-serine levels were lower in both the substantia nigra and the cerebrospinal fluid of L-DOPA free PD patients [32]. MPTP treatment increased the levels of both D-aspartate and D-serine in the putamen of the monkey. Normalization of the levels of D-serine in the substantia nigra occurred after dopaminergic denervation [32]. This suggests that there could be a possible connection between the glutamatergic and dopaminergic neurotransmission in PD and that D-serine might be implicated due to their involvement in NMDAR transmission [32]. The 2019 study is more so an extension of the 2012 one that has suggested of the possibility of a D-serine adjuvant ameliorating behavioral and motor symptoms in PD [32].

A study performed on a PD rat model found that there were disturbances in the levels of glutamate transporters in the striatum even though they attributed the enhancement in levels of D-serine content to the pathophysiology of PD [33]. The disturbances in D-serine and henceforth the alteration in the levels of D-serine were noted in the study, however [33]. By proxy of D-serine being a product of L-serine via serine racemase, L-serine could be implicated/used in the treatment of Parkinson’s disease. As such, there is great evidence pointing to the participation of the L-serine and D-serine in the pathogenesis of PD although there are contradictory assessments of the levels of these specific amino acids in the regions of the brain of PD patients.

3. 세린과 파킨슨병(PD)

L-세린은

신경 보호 특성으로 인해

간질에서 알츠하이머병(AD)에 이르는 광범위한 신경 질환을 치료하는 데

무수히 많은 방법으로 활용되어 왔습니다[27,28].

L-세린 치료는

더 이상 NMDAR을 보유하지 않거나 과발현하는 변종에서 행동, 뇌파 및 발작 빈도를

개선하는 것으로 나타났습니다 [29].

정상, 알츠하이머 및 파킨슨병 모델의 인간 측두피질에서

D-세린의 수준을 비교한 초기 연구(1993년) 중 하나에서는 큰 차이가 없는 것으로 나타났습니다 [30]. 그

러나 후속 연구에서

파킨슨병을 표적으로 하는 D-세린의 효능이 밝혀지면서

파킨슨병에서 D-세린이 어떤 역할을 하는지 시사하는 결과가 나왔습니다.

2011년의 한 연구에 따르면

D-세린과 세린 라세마제는

모두 흑질의 성상교세포와 티로신 하이드 록실라제 양성 뉴런에서 발견됩니다 [31].

D-Ser과 SR이 이러한 특정 영역에 국한되어 있다는 점에서

D-serine이 파킨슨병과 관련된 영역에도 존재할 수 있으며,

따라서 마우스 모델(MPTP/p)에서 파킨슨병이 발병하는 동안 D-ser과 SR의 수준이 어느 정도 영향을 받을 수 있다고 추측하고 있습니다 [31].

5주 동안 MPTP를 투여하여 PD를 유도한 후의 연구에서는

TH+ 뉴런의 수가 급격히 감소했음에도 불구하고

흑질의 TH+ 뉴런에서는 D-ser와 SR의 수준이 낮고 관찰되지 않았지만

선조체의 성상세포와 비도파민성 뉴런 모두에서 D-Ser와 SR의 수준이 더 높았습니다 [31].

2019년의 또 다른 연구에서도

L-DOPA가 없는 PD 환자의 흑질과 뇌척수액 모두에서

D-세린 수치가 더 낮다는 사실이 밝혀졌습니다 [32].

MPTP 치료는 원숭이의 뇌하수체에서 D-아스파르트산염과 D-세린의 수치를 모두 증가시켰습니다. 도파민성 탈신경화 후에 흑질에서 D-세린 수치가 정상화되었습니다 [32]. 이는 PD에서 글루탐산염과 도파민성 신경전달 사이에 연관성이 있을 수 있으며, D-세린이 NMDAR 전달에 관여하기 때문에 관련이 있을 수 있음을 시사합니다 [32]. 2019년 연구는 2012년에 발표된 연구의 연장선상에 있는 것으로, D-세린 보조제가 PD의 행동 및 운동 증상을 개선할 수 있다는 가능성을 제시했습니다 [32].

PD 쥐 모델에서 수행된 연구에서는 D-세린 함량의 증가가 PD의 병태생리에 기인한다고 하더라도 선조체의 글루타메이트 수송체 수준에 교란이 있음을 발견했습니다 [33]. 그러나 이 연구에서는 D-세린의 교란과 그에 따른 D-세린 수치의 변화가 관찰되었습니다 [33]. D-세린은 세린 라세마제를 통해 L-세린의 산물이기 때문에 파킨슨병 치료에 L-세린이 관여/사용될 수 있습니다.

이처럼

파킨슨병 환자의 뇌 영역에서

이러한 특정 아미노산 수치에 대한 평가가 상반되기는 하지만,

파킨슨병 발병에

L-세린과 D-세린이 관여한다는 증거가 많습니다.

4. Serines and AD

A 1995 study on the concentration of free D-serine in normal and Alzheimer’s human brain suggested that there are no significant differences between their levels [34]. However, because D-serine serves as an NMDAR agonist and the implication of NMDAR in the pathogenesis of AD, it might be counter intuitive to exclude D-serine at all. Studies have suggested that drugs used to target the function of NMDARs were able to restore some function of the subsequent downstream cascades and therefore may help in alleviating AD [35]. D-serine levels in AD were further studied in 2015 which showed increases in level of D-serine in AD patients with controls and in the experimental models of rats and mice which were developed via intracerebroventricular injections of amyloid B oligomers and APP/PS1 in the latter [35]. Amyloid-B oligomers were also found to increase D-serine and serine racemase (SR) levels [35]. However, a 2016 study seems to indicate there is no significant difference in the levels of D-serine in the cerebrospinal fluid of patients affected with AD and other dementias and therefore conclude against the use of CSF d-serine as a biomarker for AD [36]. In contrast to this, Balu et al. found that neurotoxic astrocytes indeed express serine racemase which is the precursor enzyme for the production of D-serine, belying the relational aspect of D-serine to the pathogenesis of AD [37]. A systematic review in 2020 by Chang et al. indicated the increase in levels of D-serine in the serum and CSF of patients affected with AD when compared with controls while another study done in 2020 indicated the unaltered nature of the levels of D-serine in both serum and CSF [38,39]. To complicate matters, D-serine has previously shown to help with recognition and memory in mice, learning and synaptogenesis. A 2021 study done by Piubelli et al. has found that the serum D-serine level and the D-/total serine increased significantly as AD progressed [40]. Taken altogether, we can definitely see a role that D-serine plays in the pathogenesis of AD even though the exact role and mechanism it plays remains to be determined.

The exact role L-serine plays in the pathogenesis of AD is not entirely clear since several studies that has been published appear to contradict one another. In a 2020 paper, Le Douce et al. has indicated that there is an impairment in the glycolysis-derived or de novo synthesis of L-serine in the astrocytes of mice with Alzheimer’s Disease [41]. They went on to show that the cognitive deficits that were present in AD mice were also observed after inactivation of this implicated pathway in hippocampal astrocytes and L-serine supplementation was able to rescue the cognitive deficits displayed in AD mice [41]. Chen et al. 2022 indicated in a letter to the previous paper that their research have shown how there is an increase in phosphoglycerate dehydrogenase (PHGDH) in 6 month old 3xTg AD mice and also in a widespread analysis of the database of postmortem brains of AD afflicted patients [42]. However, the initial group responded by noting that the impairment in the levels of L-serine does not necessarily indicate a decrease in the expression‎ of PHGDH and could be due to the changes in the way glycolysis is affected in early AD but not necessarily due to PHGDH expression‎. How this expression‎ of PHGDH differs between early and late AD is yet to be explored.

A 2022 study however, showed that D-cycloserine and L-serine were able to rescue some of the neurodegenerative and oxidative effects that were a result of aluminum chloride (AlCl3) induced AD in rats [28]. In both the passive avoidance test and the Morris Water Maze test, the group that was treated with either the D-cycloserine or L-serine performed better, with the L-serine group outperforming the former in the passive avoidance test [28]. Neurofibrillary tangles that are a hallmark of AD were also remarkably seen to be attenuated in the treatment groups [28]. The treatment groups also exhibited a decrease in amyloid-beta production through the lower level of expression‎ of genes related to Aβ such as APP [28]. More research needs to be done on other models of AD to further validate the efficacy of L-serine.

4. 세린과 AD

1995년에 실시된 연구에 따르면, 정상인과 알츠하이머 환자의 뇌에서 유리 D-세린의 농도에는 유의미한 차이가 없다고 합니다 [34]. 그러나 D-세린이 NMDAR의 작용제 역할을 하고, NMDAR가 AD의 발병 기전에 관여한다는 점을 고려할 때, D-세린을 아예 배제하는 것은 직관적이지 않을 수 있습니다. 연구에 따르면, NMDAR의 기능을 표적으로 하는 약물은 그 후속 하류 계통의 일부 기능을 회복시킬 수 있으므로, 알츠하이머병의 완화에 도움이 될 수 있다고 합니다 [35]. 2015년에 알츠하이머병 환자의 D-세린 수치가 더 연구되었고, 그 결과 알츠하이머병 환자에서 대조군과 쥐와 생쥐의 실험 모델에서 D-세린 수치가 증가하는 것으로 나타났습니다. 후자의 실험 모델에서는 뇌실내 주사를 통해 아밀로이드 B 올리고머와 APP/PS1을 주입했습니다 [35]. 또한, 아밀로이드-B 올리고머는 D-세린과 세린 라세마제(SR) 수치를 증가시키는 것으로 밝혀졌습니다 [35]. 그러나 2016년의 한 연구에 따르면, 알츠하이머병과 다른 치매 환자의 뇌척수액 내 D-세린 수치에는 유의미한 차이가 없으므로, CSF d-세린을 알츠하이머병의 바이오마커로 사용하는 것은 바람직하지 않다고 결론을 내렸습니다 [36]. 이와는 대조적으로, 발루 등은 신경독성 성상교세포가 실제로 D-세린 생성의 전구체 효소인 세린 라세마제를 발현한다는 사실을 발견하여, D-세린이 알츠하이머병의 발병 기전과 관련이 있다는 기존의 견해를 반박했습니다 [37]. 2020년에 Chang 등이 체계적으로 검토한 결과, 대조군과 비교했을 때, 알츠하이머병 환자의 혈청과 뇌척수액에서 D-세린 수치가 증가하는 것으로 나타났습니다. 한편, 2020년에 수행된 또 다른 연구에서는 혈청과 뇌척수액 모두에서 D-세린 수치가 변하지 않는 것으로 나타났습니다 [38,39]. 설상가상으로, D-세린은 이전에 생쥐의 인식과 기억, 학습과 시냅스 형성에 도움이 되는 것으로 나타났습니다. Piubelli 등의 2021년 연구에 따르면, 혈청 D-세린 수치와 D-/총 세린은 알츠하이머병이 진행됨에 따라 크게 증가하는 것으로 나타났습니다 [40]. 이 모든 것을 종합해 볼 때, D-세린이 알츠하이머병의 병인에서 어떤 역할을 하는지는 아직 밝혀지지 않았지만, 그 역할과 메커니즘은 분명합니다.

L-세린이 알츠하이머병의 병인에서 어떤 역할을 하는지는 여러 연구 결과가 서로 모순되는 것처럼 보이기 때문에 아직 명확하지 않습니다. 2020년 논문에서 Le Douce 등은 알츠하이머병 쥐의 성상교세포에서 L-세린의 글리콜리시스 유래 또는 de novo 합성에 장애가 있음을 밝혀냈습니다 [41]. 그들은 이어서, 알츠하이머병 쥐에서 나타난 인지 장애가 해마 성상교세포에서 이 관련 경로를 비활성화한 후에도 관찰되었으며, L-세린 보충이 알츠하이머병 쥐에서 나타난 인지 장애를 회복시킬 수 있음을 보여주었습니다 [41]. Chen et al. 2022는 이전 논문으로 보낸 편지에서 그들의 연구가 6개월 된 3xTg AD 마우스에서 포스포글리세레이트 탈수소효소(PHGDH)가 증가하는 것을 보여주고, 또한 AD로 고통받는 환자의 사후 뇌 데이터베이스에 대한 광범위한 분석에서도 같은 결과가 나왔다고 밝혔습니다 [42]. 그러나 초기 그룹은 L-세린 수치의 저하가 반드시 PHGDH 발현의 감소를 의미하는 것은 아니며, 초기 알츠하이머병에서 당분 분해의 방식의 변화 때문일 수 있지만 반드시 PHGDH 발현 때문은 아니라는 점을 지적하며 이에 대응했습니다. 초기 알츠하이머병과 후기 알츠하이머병에서 PHGDH 발현이 어떻게 다른지는 아직 밝혀지지 않았습니다.

그러나 2022년의 연구에 따르면, D-사이클로세린과 L-세린이 염화알루미늄(AlCl3)에 의해 유발된 쥐의 알츠하이머병의 일부 신경 퇴행성 및 산화 효과를 회복시킬 수 있는 것으로 나타났습니다 [28]. 수동적 회피 테스트와 모리스 수중 미로 테스트에서 D-사이클로세린 또는 L-세린으로 치료받은 그룹이 더 나은 성과를 보였으며, 수동적 회피 테스트에서 L-세린 그룹이 D-사이클로세린 그룹보다 더 우수한 성과를 보였습니다 [28]. 알츠하이머병의 특징인 신경섬유소체도 치료군에서 현저하게 감소하는 것으로 나타났습니다 [28]. 또한, 치료군은 APP와 같은 Aβ 관련 유전자의 발현 수준이 낮아짐에 따라 아밀로이드-베타 생성도 감소하는 것으로 나타났습니다 [28]. L-세린의 효능을 더 검증하기 위해서는 다른 알츠하이머병 모델에 대한 연구가 더 필요합니다.

5. Serines and Schizophrenia

Several studies have demonstrated the relationship between NMDA receptor hypofunction and schizophrenia. Blocking NMDARs in healthy people has elicited symptoms that are akin to those experience by schizophrenic patients. A post-mortem study of 101 healthy controls and 48 patients with schizophrenia were analyzed to have lower levels of the NR1 subunit and NR2C mRNA which could ultimately lead to the alternation of NMDAR stoichiometry and might point to a lower number of NMDAR in schizophrenia [43]. A research study done on serine racemase (SR −/−) knockout mice have shown to exhibit neuroanatomical and neurochemical abnormalities that are seen in schizophrenic patients such as abnormal GABA activity and glutamate signaling [44]. Levels of D-serine have been identified in several studies using the level of GRIN2A gene promoter, and found that schizophrenic patients tend to present lower levels of this gene promoter when compared with controls and the D-serine levels also follow the exact same pattern, pointing again to the possibility of D-serine pathway being implicated in the pathogenesis of schizophrenia [45].

Clinical studies have also been performed ever since to uncover the effect of the metabolism of d-serine on schizophrenia. They found that schizophrenia patients had a significantly higher serum levels of DAAO which is the enzyme responsible for the breakdown of d-serine and lower levels of both D-Serine and serine racemace (SR) [46]. A double blind placebo controlled D-serine administration also showed that D-serine at 60 mg/kg/d for 6 weeks provided improvement in the auditory mismatch negativity (MMN) in schizophrenic patients, although it is of note that this specific symptom can have both positive and negative predictive ability in the novel nature of the use of compounds such as d-serine [47]. One of the most recent studies continue to demonstrate the reduced levels of D-serine in the mouse model used to study schizophrenia have adverse effects such as utilizing the “non-ionotropic” NMDA signaling as opposed to the normal ionotropic pathway, leading to instability of the dendritic spines [48]. An early 2023 double-blind, placebo-controlled, clinical trial has also shown that D-serine supplementation of 80 and 100 mg/kg coupled with auditory cognitive remediation (AudRem) engendered an improvement in plasticity in forty-five participants with schizophrenia or schizoaffective disorder [49]. Because L-serine serves as a precursor to D-serine and is relatively innocuous, the effects supplementation of L-serine would have on patients with schizophrenia or schizoaffective disorder should be further investigated, whether it is beneficial in the same way D-serine has been based on the previous studies.

6. Serines and Epilepsy

As previously mentioned, astrocytic transmission of D-serine plays an important role in diseases that are NMDA receptor-mediated such as schizophrenia and hypoxia-ischemia [50,51]. Epilepsy particularly status epilepticus (SE) is noted to have prolonged seizure activity that induces hypoxia which becomes severe enough to cause encephalopathy [52]. As such, this form of epilepsy can cause death of neuronal cells, astroglia and epileptogenesis [53,54]. It has also been reported that astroglia death occurred after reactive microgliosis but before damage was inflicted on the neurons in the rat dentate gyrus in pilocarpine-induced SE models [55]. Because D-serine is implicated in glia-to-neuron signaling, it is important to understand the role gliotransmission mediated by D-serine plays in epileptogenesis or seizure activity. A study in 2010 investigated the role D-serine plays in epileptogenesis or seizure activity and deciphered the relationship between the glial responses in the spatiotemporal lobe and the D-serine/serine racemase system within the mesial temporal structures after an SE [56]. Seizure was induced in 9 weeks old male Sprague-Dawley (SD) rats via treatment with lithium chloride and were then given pilocarpine after 20 h [56]. SE is typically observed within 20–30 min after treatment with pilocarpine [56]. The animals are then placed in close observation for about 3 to 4 h daily to check in for behavioral changes and consequent occurrences of seizures for 4 weeks [56]. The brains were then collected. Interestingly, there is a mismatch between D-serine and Serine Racemase Immunoreactivities in the rat hippocampus [56]. Because racemase activity is the main pathway in which D-serine is synthesized under normal conditions, serine racemase immunoreactivity is expected to be colocalized with D-serine. However, the study observed the colocalization with nestin and vimentin instead of D-serine at 1 week after SE [56].

Since SE is not under normal conditions, serine racemase is surmised to function as an eliminase in conditions that are low in ATP [56]. 4 weeks after SE, the immunoreactivity of D-serine was heightened in astrocytes followed by an increase in immunoreactivity of serine racemase [56]. Moreover, in astrocytes, PLK and PNPO immunoreactivities, the PLP synthetic enzymes that act as cofactors in the conversion of L-serine to D-serine, are now also colocalized with SR immunoreactivity [56]. This indicates that D-serine synthesis is increased via serine racemase activations with PLP playing an indirect role in the NMDA receptor-mediated neuronal excitability in rats [56]. Astroglial D-serine Immunoreactivity is also seen to be increased in the rat hippocampus after an SE such that it was higher in the hippocampus proper and hilus 1 week after SE and in the astrocytes in the CA1 region and the dentate gyrus at four weeks after SE, suggesting that astrocytes maybe employing epileptiform discharges through increase in release of D-serine [56]. The study shows how D-serine is implicated in neuronal hyperexcitability and how serine racemase activity might play a part in the way immature astrocytes migrate and differentiate [56].

A study in 2020, however indicated that D-serine might play a role in ameliorating the loss of neuronal cells in temporal lobe epilepsy (TLE) [57]. Pilocarpine was used to induce SE in adult rats and the animals were monitored for seizures and behavioral changes. D-serine was supplied to the animals via mini osmotic pumps and was shown to decrease the number and severity of frank seizures when compared to that of vehicle [57]. The D-serine treatment was also able to rescue the loss of neurons even though the infusion was performed unilaterally into the right hemisphere [57]. Additionally, in order to identify the source of endogenous D-serine in the medial entorhinal area (MEA), the expression‎ of serine racemase (SR) was investigated [57]. Both neurons and astrocytes were positive for serine racemase, indicating that both can be sources of D-serine except for some neurons which could be GABAergic interneurons [57]. In addition to this, the level of D-serine in the epileptic brain is identified through the use of chiral micellar electrokinetic chromatography (MEKC) [57]. Even though total D-serine might be similar between the two conditions (control vs. epileptic), the level of ambient D-serine particularly in the extracellular compartments is deficient in TLE [57].

A subsequent study in 2021 performed immunofluorescence staining and western blotting to identify the expression‎ patters of D-serine and NMDA receptor 1 in patients with intractable epilepsy [58]. The level of D-serine was greater in the neurons and glial cells in patients afflicted with intractable epilepsy than in control participants [58]. The mean absorbance of NMDA receptor 1 was also higher in patients with intractable epilepsy when compared with control participants, indicating the possible implication of this pathway in the Epileptogenesis [58]. The implication of D-serine in Epileptogenesis is certain but how this happens remains to be elucidated. Are the different forms of epilepsy responsible for the varying levels of D-serine observed in the aforementioned studies? Could the levels be attributed to the different timepoints each epileptic event is measured at?

7. Serines and Multiple Sclerosis (MS)

Not much is currently known regarding multiple sclerosis since the entire mechanism of MS has yet to be fully elucidated. However, due to the nature of MS being an inflammatory disease and the immune system and its derived cells requiring constant nutrients to maintain their functions, amino acid pathways that contribute to this homeostatic functioning could be implicated in mitigating the symptoms of the disease. Serine/threonine kinases have been demonstrated to be utilized by cells to sense the levels of amino acids particularly the GCN2K and the mammalian target of rapamycin (mTOR) pathway [59]. A lower level of amino acid will cause a deacetylation of tRNAs and these tRNAs will activate GCN2K [60]. The kinase will then phosphorylate Ser 51 of eukaryotic initiation factor 2 (eIF2α)-associated 67-kDa glycoprotein which is required to initiate translation in eukaryotes [61]. Even though the direct effects of L-serine in MS are yet to be fully known, it is an area that has room for great exploration since amino acid homeostasis is important in the process of inflammation.

8. Clinical Studies on L-serine and Neurological Diseases

There have not been widespread clinical studies done on L-serine since most if not all have focused directly on D-serine. However, recent studies have shown that d-serine might have a longer time to diffuse through the blood-brain barrier and might even engender nephrotoxicity [41,62]. Worse yet, long term effects of d-serine are still not entirely known. In contrast to this, L-serine has been approved for use by the FDA [9,63]. Several clinical studies however has been done on L-serine, the first of which was on Hereditary sensory neuropathy type 1 (HSAN1). L-serine supplementation of 400 mg/kg/day for 52 weeks was able to reduce the neurotoxic level of 1-deoxysphingolipds which is responsible for the degeneration without causing other metabolic side effects [64]. A phase I clinical trial was also performed on Amyotrophic Lateral Sclerosis (ALS) patients to uncover the efficacy of oral L-serine supplementation [65]. They were able to find that L-serine did not pose a threat to the patients and did not appear to contribute to the rate of decline. A phase II trail is now planned to investigate the effects [65]. The aforementioned GRIN2B gene autosomal dominant mutations have led to severe encephalopathy and was seen in a 5 year old patient who had severe encephalopathy. The GluN2B-containing NMDARs were found to have a smaller pore size through structural modeling and thorough expression‎ on cellular models appeared to have lower glutamate affinity [65]. Because the naturally occurring d-serine tend to restore the levels of NMDAR activity, L-serine was started on the patient and the patient exhibited improvement in motor and cognitive performance and even communication after 11 and 17 month of supplementation [65].

A similar clinical study was performed on 2 female patients, one 18 months old and the other 4 years old to investigate the effects of L-serine supplementation (500 mg/kg/day in 4 doses) in GRIN2B-related neurodevelopmental disorder that arises out of a loss of function of GRIN2B gene [66]. The GluN2B-containing NMDARs no longer functions well due to this. One patient was seen to exhibit improvements in psychomotor development and caregivers report noticing increased alertness and better communication skills [66].

However, more studies need to be performed before we can safely apply the usage of L-serine for the wide variety of neurological diseases that we have outlined above. L-serine due to its relatively safe-to-use nature left us with an open field of utilization for all applications. A summary of the current research regarding serines and neurological and neurodegenerative disorders are displayed in Table 1.

8. L-세린과 신경계 질환에 대한 임상 연구

L-세린에 대한 임상 연구는 광범위하게 수행되지 않았으며,

대부분의 연구가 D-세린에 직접적으로 초점을 맞추었기 때문입니다.

그러나

최근 연구에 따르면

D-세린은 혈액-뇌 장벽을 통과하는 데 더 오랜 시간이 걸리며

심지어 신독성을 유발할 수도 있다고 합니다[41,62].

더 심각한 문제는

d-세린의 장기적인 영향이 아직 완전히 밝혀지지 않았다는 점입니다.

이와는 대조적으로

L-세린은 FDA에서 사용 승인을 받았습니다[9,63].

그러나

L-세린에 대한 여러 임상 연구가 수행되었는데,

그 중 첫 번째 연구는 유전성 감각 신경병증 1형(HSAN1)에 대한 것이었습니다.

52주 동안 400 mg/kg/일의 L-세린 보충제를 섭취한 결과,

다른 대사 부작용 없이 퇴행을 유발하는

1-데옥시스핑고리프드의 신경 독성 수치를 감소시킬 수 있었습니다 [64].

근위축성 측삭 경화증(ALS) 환자를 대상으로 한 임상 1상 시험에서도

경구용 L-세린 보충제의 효능을 확인하기 위해 실시되었습니다 [65].

연구진은

L-세린이 환자에게 위협이 되지 않으며

병의 진행 속도에 영향을 미치지 않는다는 사실을 발견할 수 있었습니다.

현재 그 효과를 조사하기 위한

2상 임상시험이 계획되어 있습니다[65].

앞서 언급한 GRIN2B 유전자 상염색체 우성 돌연변이는 중증 뇌병증을 유발하며, 중증 뇌병증을 앓고 있던 5세 환자에게서 나타났습니다. 구조 모델링을 통해 글루N2B를 함유한 NMDAR은 기공 크기가 더 작은 것으로 밝혀졌으며, 세포 모델에서 철저히 발현하면 글루타메이트 친화성이 더 낮은 것으로 나타났습니다 [65]. 자연적으로 발생하는 d-세린은 NMDAR 활성 수준을 회복시키는 경향이 있기 때문에 환자에게 L-세린을 투여한 결과, 11개월과 17개월 후 운동 및 인지 능력이 향상되고 심지어 의사소통까지 개선되었습니다 [65].

GRIN2B 유전자의 기능 상실로 인해 발생하는 GRIN2B 관련 신경 발달 장애에 대한 L-세린 보충제(500 mg/kg/일 4회 투여)의 효과를 조사하기 위해 18개월과 4세의 여성 환자 2명을 대상으로 유사한 임상 연구가 수행되었습니다 [66]. 이로 인해 GluN2B 함유 NMDAR이 더 이상 제대로 기능하지 못합니다. 한 환자는 정신 운동 발달이 개선된 것으로 나타났으며 간병인은 주의력이 증가하고 의사소통 능력이 향상되었다고 보고했습니다 [66].

그러나 위에서 설명한 다양한 신경 질환에 L-세린을 안전하게 적용하기 위해서는 더 많은 연구가 필요합니다.

비교적 안전하게 사용할 수 있는

L-세린의 특성으로 인해

모든 응용 분야에 활용할 수 있는 가능성이 열려 있습니다.

세린과 신경계 및 신경 퇴행성 질환에 관한

최신 연구 요약은 표 1에 나와 있습니다.

Table 1

Overview of the Serine-related research studies.

DiseaseArea of ResearchEffectsReferences

Parkinson’s Disease (PD)	D-serine	D-serine rescued/mitigated some behavioral and motor deficits caused by PD	[32]
Alzheimer’s Disease (AD)	D-serine levels	Conflicting	[37,38,39]
	L-serine	Conflicting (PHGDH vs. L-serine)	[41,42]
Epilepsy	Astroglial D-serine immunoreactivity	Increase in the level of D-serine via epileptiform discharges in astrocytes	[56]
	D-serine’s role in temporal lobe epilepsy (TLE)	Mitigated loss of neurons, ambient D-serine depleted in TLE, and similar total D-serine	[57]
	Expression‎ patterns of D-serine and NMDA receptor 1 in patients with intractable epilepsy	Both levels higher in patients with intractable epilepsy	[58]
Multiple Sclerosis	Amino acid homeostasis.	N/A	-
Schizophrenia	Serine racemace (SR) knockout.	Exhibit neuroanatomical and neurochemical abnormalities that are seen in schizophrenic patients	[44]
	D-serine at 60 mg/kg/d for 6 weeks.	Improvement in auditory mismatch negativity	[47]
Amyotrophic Lateral Sclerosis (ALS), Hereditary Sensory and Autonomic Neuropathy (HSAN) Type 1C, and Severe Encephalopathy	L-serine administered to patients with severe encephalopathy	Improvement in motor and cognitive performance and even communication after 11 and 17 months of supplementation	[62]
	L-serine supplementation of 400 mg/kg/day for 52 weeks	Reduced the neurotoxic level of 1-deoxysphingolipds	[64]
	L-serine phase I trial on ALS patients	Did not appear to contribute to the rate of decline, so phase II was started	[65]

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Figure 1

L-serine synthesis via the phosphorylated pathway [67] and its effects on the body.

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9. Conclusions and Future Directions

Literature up until this point has been concentrated on the study of D-Serine but because of its toxic nature and underreported long-term effects, L-serine might be a useful substitute as it is a precursor to D-Serine. However, it is important to also understand the levels of serine racemase (SR) in the neurological diseases that we listed above because the enzyme serine racemase is needed to convert L-serine to D-serine and if the level of SR is already low in patients which it was in a study shown above, L-serine use might be to no avail. The pathway remains an area that could be used to target a wide range of neurological and neurodegenerative diseases but it is crucial to pay attention to the ages of the animals we conduct our experiments on since diseases such as Alzheimer’s are age-related and in some ways Parkinson’s. The levels of these amino acids and enzymes could differ vastly among the age ranges and lead us to conclude without much basis. Even though this may be the case, the purported benefits of L-serine due to its position in the pathway allows for a wide field of usage and potentially be employed to elicit a great deal of beneficiary effects. As such, a greater but carefully measured emphasis should be placed on uncovering the exact ways in which L-serine work particularly in the pathogenesis of certain neurological and neurodegenerative diseases and the baseline levels of the different agents, both enzymes (such as PHGDH and Serine Racemase) and substrate s(both L-serine and D-serine) that are involved in the pathway at different timepoints.

9. 결론 및 향후 방향

지금까지의 문헌은 

D-세린에 대한 연구에 집중되어 있지만, 

독성이 있고 장기적인 영향에 대한 보고가 부족하기 때문에 

D-세린의 전구체인 L-세린이 유용한 대체제가 될 수 있습니다. 

그러나 위에 나열한 

신경계 질환의 세린 라세마제(SR) 수치를 이해하는 것도 중요한데, 

이는 L-세린을 D-세린으로 전환하려면 세린 라세마제 효소가 필요하고 

위에 소개한 연구처럼 환자의 SR 수치가 이미 낮다면 

L-세린을 사용해도 소용이 없을 수 있기 때문입니다. 

이 경로는 광범위한 신경 및 신경 퇴행성 질환을 표적으로 삼을 수 있는 영역이지만 알츠하이머와 같은 질환은 연령과 관련이 있고 어떤 면에서는 파킨슨병과도 관련이 있기 때문에 실험을 수행하는 동물의 연령에 주의를 기울이는 것이 중요합니다. 

이러한 아미노산과 효소의 수치는 연령대에 따라 크게 달라질 수 있으므로 근거 없이 결론을 내릴 수 있습니다. 그렇더라도, L-세린의 효능은 경로에서 차지하는 위치로 인해 광범위한 분야에서 사용될 수 있으며 잠재적으로 많은 효과를 이끌어내는 데 사용될 수 있습니다. 따라서 특정 신경 및 신경 퇴행성 질환의 발병 기전에서 L-세린이 작용하는 정확한 방식과 이 경로에 관여하는 다양한 효소(PHGDH 및 세린 라세마제 등)와 기질(L-세린과 D-세린 모두)의 기저 수준을 다른 시점에서 신중하게 측정하여 밝혀내는 데 중점을 두어야 합니다.

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Acknowledgments

The authors would like to recognize the critical feedback and insightful comments from all members of the Sun Lab that helped conceive this manuscript.

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Abbreviations

AD	Alzheimer’s Disease
ALS	Amyotrophic Lateral Sclerosis
CSF	Cerebrospinal Fluid
DAAO	D-amino acid oxidase
EEG	Electroencephalography
GCN2K	General Control Nonderepressible2 Kinase
GRIN2B	Glutamate(NMDA) Receptor Subunit Epsilon-2
HSAN1	Hereditary sensory neuropathy type 1
MMN	Mismatch Negativity
MPTP	(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)
mTOR	Mammalian Target of Rapamycin
mTORC1	Mammalian Target of Rapamycin Complex 1
NK Cells	Natural Killer Cells
NMDAR	N-methyl D-aspartate receptor
PD	Parkinson’s Disease
PHGDH	Phosophoglycerate Dehydrogenase
PLP	Pyridoxal Phosphate
PPAR-y	Peroxisome Proliferator-activated Receptor Gamma
PSAT	Phosphohydroxythreonine Aminotransferase
PSP	Phosphoserine Phosphatase
SE	Status Epilepticus
SR	Serine Racemase
TH+	Tyrosine Hydroxylase-positive

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Funding Statement

This work was supported in part by the National Institute on Aging grants AG082327, AG057734, AG050225, and R21AG082327 (L.Y.S.).

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