Neuronal Autophagy: a Cell-Autonomous Protection Mechanism

描述（由申请人提供）：巨噬（自噬）是一种受调控的细胞“自噬”过程，它将一部分细胞质隔离到双膜液泡（自噬体）中，并将自噬体递送给溶酶体降解。自噬途径先前涉及多种生理过程以及人类病理状况，如癌症，传染病，衰老和神经退行性变。我们的长期目标是阐明神经元自噬的分子和细胞过程，了解神经退行性疾病发病机制中自噬失调的分子基础，并评估自噬作为治疗目的的药物靶点。最近的研究，包括我们的研究，已经证明神经细胞含有基础水平的自噬，并且这种构成性自噬具有神经保护作用。我们最近的研究还揭示了自噬在预防轴突营养不良和变性方面的一个重要的、以前未被认识到的细胞自主功能。我们的初步假设是，自噬活动在神经元中是高度区隔的，并在轴突中受到特异性调节。基于我们的发现，轴突自噬对于维持生理状态下的轴突稳态是必不可少的，我们还假设轴突自噬受损可能导致与许多人类神经系统疾病相关的轴突病。此外，目前的证据已将自噬途径与细胞中易于聚集蛋白（如1-synuclein A53T突变体）的降解和毒性积累联系起来。我们进一步假设自噬活动可以改变疾病过程，多巴胺能神经元的缺乏易导致帕金森病的发病机制。因此，我们的具体目标是：(1)解剖神经元轴突的自噬过程和轴突自噬的控制机制；(2)研究轴突自噬清除疾病相关蛋白的机制及疾病相关蛋白干扰轴突自噬的潜在致病机制；(3)确定自噬不足促进中脑多巴胺能神经元中1-突触核蛋白的年龄相关性毒性积累、氧化应激和神经元死亡。我们的研究有望深入了解神经元或轴突自噬的具体过程和调控机制，为了解轴突病的发病机制和评价自噬作为治疗帕金森病等神经退行性疾病的药物靶点提供有价值的信息。公共卫生相关性：本项目的目的是阐明神经元自噬的分子和细胞过程，这与神经退行性疾病的致病机制有关。我们将研究功能失调的自噬与帕金森病病理过程的关系，并进一步评估自噬作为治疗帕金森病的药物靶点。

DESCRIPTION (provided by applicant): 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 1-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 1-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. PUBLIC HEALTH RELEVANCE: 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.