Re: Autophagy in axonal and dendritic degeneration

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Autophagy in axonal and dendritic degeneration.pdf

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Volume 36, Issue 7, July 2013, Pages 418-428

Review

Autophagy in axonal and dendritic degeneration

Author links open overlay panelYi Yang 1 2 3, Michael Coleman 4, Lihui Zhang 1, Xiaoxiang Zheng 2 3, Zhenyu Yue 5

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https://doi.org/10.1016/j.tins.2013.04.001Get rights and content

Degeneration of axons and dendrites is a common and early pathological feature of many neurodegenerative disorders, and is thought to be regulated by mechanisms distinct from those determining death of the cell body. The unique structures of axons and dendrites (collectively neurites) may cause them to be particularly vulnerable to the accumulation of protein aggregates and damaged organelles. Autophagy is a catabolic mechanism in which cells clear protein aggregates and damaged organelles. Basal autophagy occurs continuously as a housekeeping function, and can be acutely expanded in response to stress or injury. Emerging evidence shows that insufficient or excessive autophagy contributes to neuritic degeneration. Here, we review the recent progress that has begun to reveal the role of autophagy in neurite function and degeneration.

Introduction

Neurons comprise the soma, axons, and dendrites. The latter two are collectively known as neurites, in which molecules including proteins are synthesized, delivered, and degraded for their dynamic functions in synaptic growth and activity. Upon specific stimuli, the axons and dendrites of cultured neurons exhibit features of degeneration, including terminal degradation, neurite retraction, synaptic pathology, and marked focal beading or swelling. The term ‘dystrophic neurites’ is used to describe these processes, and is analogous to neurite dystrophy in vivo. In neurodegenerative disorders, axons, dendrites, and synapses often degenerate before the loss of the cell bodies, and this may contribute to preclinical episodes of disease process and eventual clinical symptoms 1, 2.

Autophagy is a self-digestion system that is responsible for the clearance of long-lived proteins and damaged organelles by the lysosome. A group of evolutionarily conserved gene products, known as the Atg (autophagy-related gene) proteins, are required for autophagosome (autophagic vacuole; see Glossary) synthesis, maturation, trafficking, and clearance [3]. Several functionally distinct groups are responsible for autophagy execution, including the Ulk1–Atg13–FIP200 kinase complex, the class III phosphoinositide 3-kinase (PI3K-III) complex containing the core proteins Vps34, p150, and beclin 1, the lipid-binding Atg18 homologs, the multi-spanning transmembrane protein Atg9, the Atg12 conjugation system, and the ubiquitin-like LC3 conjugation system [3]. Examples of upstream signaling molecules that regulate autophagy activity include the mammalian target of rapamycin (mTOR), a Ser/Thr kinase which prevents autophagy induction through Ulk1 inactivation, and AMP-activated protein kinase (AMPK), an energy-sensing kinase that promotes autophagy by inducing Ulk1 activation [4]. Pharmacological induction of autophagy can be achieved using rapamycin, which inhibits mTOR. In addition, the class III PI3K–beclin 1 complex controls the nucleation process of the phagophore, a precursor of the autophagosome. 3-Methyladenine (3-MA), or wortmannin, which inhibit class III PI3K activity, are often used to block autophagy.

Emerging evidence demonstrates that macroautophagy (hereafter referred to as ‘autophagy’) plays a critical role in the maintenance of protein and organelle homeostasis in the axons and protection of axons. Dysfunctional autophagy has been observed in experimental neuritic degeneration in both primary neuronal cultures 5, 6, 7 and in vivo animal models 8, 9, 10, 11, 12, 13. Insufficient autophagic clearance, and perhaps excessive autophagy induction, characterized by the accumulation of autophagy-related vesicular compartments, are also observed in degenerating neurites of brain specimens from patients with neurodegenerative disease including Alzheimer's disease (AD) 14, 15, 16, 17, Parkinson's disease (PD) 18, 19, and Huntington's disease (HD) [20]. A growing body of evidence demonstrates the indispensable role of constitutive autophagy in preventing neuritic degeneration, whereas imbalanced induction of autophagy can also contribute to neuritic degeneration. This review focuses on current progress that has begun to reveal autophagic processes in the axons and dendrites. The roles for autophagy in neuronal death and neurological disorders, and the potential molecular mechanisms underlying the pathogenic function of autophagy, have recently been reviewed 21, 22, 23.