Neuronal Autophagy: a Cell-Autonomous Protection Mechanism

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Abstract Macroautophagy (autophagy) is a regulated, cellular ¿self-eating¿ process that sequesters a portion of cytoplasm into double membrane vacuoles (autophagosomes) and delivers autophagosomes to lysosomes for degradation. Autophagic pathway has previously been implicated in a variety of physiological processes as well as human pathological conditions such as cancer, infectious diseases, ageing and neurodegeneration. Our long-term goal is to elucidate the molecular and cellular process of neuronal autophagy, to understand molecular basis of deregulated autophagy which underlies the pathogenic mechanisms of neurodegenerative diseases, and to evaluate autophagy as drug target for therapeutic purpose. Recent studies, including ours, have demonstrated that neural cells contain basal level of autophagy and that this constitutive autophagy is neuro-protective. Our recent study has also revealed an important, previously unrecognized cell-autonomous function of autophagy in the prevention of axonal dystrophy and degeneration. Our primary hypothesis is that autophagic activity is highly compartmentalized in neuron and is specifically regulated in the axons. Based our findings that axonal autophagy is indispensable for the maintenance of axonal homeostasis under physiological condition, we also hypothesize that compromised axonal autophagy can contribute to the axonopathies which are associated with a number of human neurological disorders. Moreover, current evidence has linked autophagic pathway to the degradation and prevention of toxic accumulation of aggregate-prone proteins (such as ?-synuclein A53T mutant) in the cells. We further hypothesize that autophagic activity can modify the disease process and that deficiency in dopaminergic neurons predisposes to the pathogenesis of Parkinson's disease. Thus, our specific aims are to (1) dissect neuronal autophagic process in the axons and control mechanism of axonal autophagy; (2) investigate the autophagic clearance of disease-associated proteins from the axons and potential pathogenic mechanism mediated by disease-associated proteins in perturbing axonal autophagy; (3) determine that deficiency in autophagy promote the age-related toxic accumulation of ?-synuclein, oxidative stress and neuronal death in the midbrain dopaminergic neurons. Our proposal is expected to provide insight into specific autophagic process and the regulation of autophagy in neuron or axons, and will provide valuable information for the understanding of pathogenic mechanism of axonopathy and the evaluation of autophagy as drug target for the treatment of neurodegenerative disease such as Parkinson's disease. The goal of this project is to elucidate the molecular and cellular process of neuronal autophagy which has been implicated in the pathogenic mechanisms of neurodegenerative diseases. We will investigate how dysfunctional autophagy is connected to the pathological process in Parkinson's disease and further evaluate autophagy as drug target for the treatment of Parkinson's disease.