Regulation of neuronal autophagy in axon: implication of autophagy in axonal function and dysfunction/degeneration.
Autophagy has recently emerged as potential drug target for prevention of neurodegeneration. However, the details of autophagy process and regulation in the central nervous system (CNS) are unclear. By using a neuronal excitotoxicity model mice, we engineered expression of a fluorescent autophagic marker and systematically investigated autophagic activity under neurodegenerative condition. The study reveals an early response of Purkinje cells to excitotoxic insult by induction of autophagy in axon terminals, and that axonal autophagy is particularly robust in comparison to the cell body and dendrites. The accessibility of axons to rapid autophagy induction suggests local biogenesis of autophagosomes in axons. Characterization of functional interaction between autophagosome protein LC3 and microtubule-associated protein 1B (MAP1B), which is involved in axonal growth, injury and transport provides evidence for neuron or axon-specific regulation of autophagosomes. Furthermore, we propose that p62/SQSTM1, a putative autophagic substrate can serve as a marker for evaluating impairment of autophagic degradation, which helps resolve the controversy over autophagy levels under various pathological conditions. Future study of the relationship between autophagy and axonal function (e.g., transport) will provide insight into the mechanism underlying axonopathy which is directly linked to neurodegeneration.
Yue
Zhenyu
Z
Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA. zhenyu.yue@mssm.edu
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D001343:Autophagy; D001369:Axons / Q000473:pathology* / Q000502:physiology*; D001692:Biological Transport; D006360:Heat-Shock Proteins / Q000378:metabolism; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008954:Models, Biological; D009410:Nerve Degeneration; D010588:Phagosomes / Q000378:metabolism; D000071456:Sequestosome-1 Protein
D048868:Adaptor Proteins, Signal Transducing; D006360:Heat-Shock Proteins; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse