Neuronal Autophagy: a Cell-Autonomous Protection Mechanism

描述(申请人提供)：巨型自噬(自噬)是一种受调控的细胞“自噬”过程，它将部分细胞质隔离成双膜空泡(自噬小体)，并将自噬小体运送到溶酶体内进行降解。自噬途径以前被认为与多种生理过程以及人类的病理状况有关，如癌症、传染病、衰老和神经变性。我们的长期目标是阐明神经元自噬的分子和细胞过程，了解放松调节的自噬的分子基础，这是神经退行性疾病发病机制的基础，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，并且这种结构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中的一个重要的、以前未被认识的细胞自主功能。我们的主要假设是，自噬活动在神经元中高度区域化，并在轴突中受到特定的调节。基于我们的发现，轴突自噬对于维持生理条件下轴突的动态平衡是不可或缺的，我们还假设，轴突自噬受损可能导致与许多人类神经疾病相关的轴突病变。此外，目前的证据已将自噬途径与降解和防止聚集倾向蛋白(如1-突触核蛋白A53T突变体)在细胞中的毒性积累联系在一起。我们进一步假设，自噬活动可以改变疾病的过程，多巴胺能神经元的缺陷容易导致帕金森氏病的发病。因此，我们的具体目标是：(1)解剖轴突中神经元的自噬过程和轴突自噬的控制机制；(2)研究疾病相关蛋白从轴突中的自噬清除以及疾病相关蛋白介导的扰乱轴突自噬的潜在致病机制；(3)确定自噬缺陷促进中脑多巴胺能神经元中与年龄相关的1-突触核蛋白的毒性积累、氧化应激和神经元死亡。我们的建议有望为深入了解神经元或轴突中特定的自噬过程和自噬的调控提供有价值的信息，并将为理解轴索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：该项目的目标是阐明神经元自噬的分子和细胞过程，该过程与神经退行性疾病的发病机制有关。我们将研究功能失调的自噬如何与帕金森病的病理过程相联系，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.