Regulation of Autophagic Cell Death in Neurons

描述（由申请人提供）：帕金森氏症、阿尔茨海默氏症和亨廷顿氏症患者的死后脑组织显示出自噬增加的迹象（Cataldo等人，1996；Anglade等人，1997；Kegel等人，2000；Nixon等人，2000）。自噬是一种受到严格控制的生存反应，在缺乏营养的细胞中被激活，作为将营养物质（如核苷酸和氨基酸）再循环回细胞的一种手段（Levine and Yuan, 2005）。然而，自噬通路的解除可能有助于神经退行性疾病的发病机制（Nixon, 2006； Martinez-Vicente和Cuervo， 2007）。此外，像Fas这样的促死亡信号可能刺激自噬，从而加速这一过程，从而增强细胞凋亡和自噬诱导的神经元死亡（Levine and Yuan, 2005）。将自噬从神经保护反应转变为有害反应的细胞信号事件正在积极研究中。旨在控制神经退行性变过程中自噬反应的治疗可能会减缓神经元丧失的进展，从而允许受损神经元的恢复和修复。事实上，神经营养因子已被证明可以调节自噬。我们实验室的初步数据表明，IGF-1减少了大自噬空泡的积累，抑制了小脑浦肯野神经元自噬介导的死亡。我们假设igf -1抑制自噬诱导的小脑浦肯野神经元细胞死亡不是通过阻断自噬囊泡的形成，而是通过加速自噬通量，从而允许更快的氨基酸循环和营养因子剥夺细胞的恢复。本研究的第一个目的是确定IGF-1是否调节自噬液泡的形成、积累和/或与溶酶体的融合。第二个目的将探讨IGF-1是否通过自噬途径影响通量以提高自噬效率。第三个具体目标将开始解决igf -1的作用机制，并研究gsk -3 β在自噬调节中的潜在新作用。了解控制这些神经元自噬细胞死亡的分子机制以及神经营养因子如何调节自噬，可能为设计新的神经退行性疾病治疗策略提供理论基础。

DESCRIPTION (provided by applicant): Human post mortem brain tissue from patients with Parkinson's, Alzheimer's and Huntington's disease demonstrate signs of increased autophagy (Cataldo et al., 1996; Anglade et al., 1997; Kegel et al.,2000; Nixon et al.,2000). Autophagy is a tightly controlled survival response activated in nutrient deprived cells as a means for recycling nutrients (e.g.nucleotides and amino acids) back to the cell (Levine and Yuan, 2005). However, deregulation of the autophagic pathway may contribute to the pathogenesis of neurodegenerative diseases (Nixon, 2006; Martinez-Vicente and Cuervo, 2007). Furthermore, it is possible that pro-death signals like Fas stimulate autophagy, which accelerates this process resulting in enhanced apoptotic and autophagic- induced neuronal death (Levine and Yuan, 2005). The cell signaling events that switch autophagy from a neuroprotective to a detrimental response are under active investigation. Therapies aimed at controlling the autophagic response during neurodegeneration may slow the progression of neuronal loss allowing for the recovery and repair of damaged neurons. Indeed, neurotrophic factors have been shown to regulate autophagy. Preliminary data from our lab demonstrates that IGF-1 reduces the accumulation of large autophagic vacuoles and inhibits autophagic-mediated death of cerebellar purkinje neurons. We hypothesize that IGF-1inhibits autophagic-induced cell death of cerebellar Purkinje neurons not by blocking formation of autophagic vesicles, but rather by accelerating autophagic flux, thus allowing for faster recycling of amino acids and recovery in trophic factor deprived cells. The first aim of this proposal will determine whether IGF-1 regulates autophagic vacuole formation, accumulation and/or fusion with the lysosome. The second aim will address whether IGF-1 effects flux through the autophagic pathway to increase autophagy efficiency. The third specific aim will begin to address the mechanism of IGF-1action and investigate a'potential novel role for GSK-3beta in the regulation of autophagy. Understanding the molecular mechanisms that control autophagic cell death in these neurons and how neurotrophic factors regulate autophagy may form a rationale basis for the design of new therapeutic strategies for neurodegeneration.