alpha-synuclein and protein degradation

α-突触核蛋白和蛋白质降解

基本信息

  • 批准号:
    7296143
  • 负责人:
  • 金额:
    $ 11.8万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2006
  • 资助国家:
    美国
  • 起止时间:
    2006-09-30 至 2009-04-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Parkinson's Disease (PD) is a major health burden on the ageing population in the United States and elsewhere. The identification of gene defects that cause the disease in rare families may lead to new insights into the pathophysiology of the more common sporadic forms. One particular gene linked to PD that is especially relevant to the sporadic disease is alpha-synuclein (ASYN), as its protein product is the major component of Lewy Bodies. Furthermore, multiplication of the ASYN locus is sufficient to cause PD in humans. Therefore, elucidating the normal and aberrant functions of ASYN, as well as the manner of its regulation, may lead to a better understanding of the pathophsyiology of PD and the development of novel therapies. We have previously found that mutant ASYN can impair protein degradation through the lysosomes and the ubiquitin-proteasome system. Defects of protein handling may also occur in other genetic or sporadic forms of PD, and may form a common pathophysiological basis for this disorder. We have proposed that the impact on the lysosomes may be mediated by an inhibition by mutant ASYN of the pathway of Chaperone-Mediated Autophagy (CMA), which normally degrades ASYN. However, these results were largely achieved in an artificial setting, and the degradation of ASYN and its impact on proteolytic systems is controversial. We propose to first establish that ASYN is degraded by CMA in neuronal cells, by manipulating Lamp2a, the receptor for CMA and its rate-limiting step, and by examining the degradation of ASYN when it is not targeted to the CMA pathway. Mutant ASYNs that do not affect CMA will also be examined for their relative toxic effects, to ascertain whether ASYN toxicity is mediated in part by CMA blockade. We have recently found that ASYN can be secreted and exert toxic effects, and we will examine whether such toxicity, which may be physiologically relevant, is related to the inhibition of UPS and/or lysosomal function in neuronal cells. Lastly, we will examine whether the effects of ASYN on protein degradation systems in neuronal cell lines are applicable in primary neuronal cell cultures. These studies will help to decipher the post-translational regulation of ASYN levels, which is critical for its steady-state levels and its impact on neuronal physiology, and its effects on protein degradation pathways, which may be critical for its pathogenic effects.
描述(由申请人提供):帕金森病 (PD) 是美国和其他地区老龄化人口的主要健康负担。在罕见家族中鉴定出导致该疾病的基因缺陷可能会给更常见的散发性疾病的病理生理学带来新的见解。 α-突触核蛋白 (ASYN) 是一种与 PD 相关且与散发性疾病密切相关的特殊基因,因为其蛋白质产物是路易体的主要成分。此外,ASYN 基因座的增殖足以引起人类 PD。因此,阐明 ASYN 的正常和异常功能及其调节方式,可能有助于更好地了解 PD 的病理生理学和开发新疗法。我们之前发现突变的 ASYN 可以通过溶酶体和泛素蛋白酶体系统损害蛋白质降解。蛋白质处理缺陷也可能发生在其他遗传性或散发性帕金森病中,并且可能形成这种疾病的共同病理生理学基础。我们提出,对溶酶体的影响可能是通过突变体 ASYN 对伴侣介导的自噬 (CMA) 途径的抑制来介导的,该途径通常会降解 ASYN。然而,这些结果很大程度上是在人工环境下实现的,ASYN 的降解及其对蛋白水解系统的影响存在争议。我们建议首先通过操纵 CMA 受体 Lamp2a 及其限速步骤,并通过检查 ASYN 不靶向 CMA 途径时的降解情况,首先确定 ASYN 在神经元细胞中被 CMA 降解。不影响 CMA 的突变 ASYN 也将检查其相对毒性作用,以确定 ASYN 毒性是否部分由 CMA 阻断介导。我们最近发现ASYN可以分泌并发挥毒性作用,我们将检查这种可能与生理相关的毒性是否与抑制神经元细胞中的UPS和/或溶酶体功能有关。最后,我们将检查 ASYN 对神经元细胞系中蛋白质降解系统的影响是否适用于原代神经元细胞培养物。这些研究将有助于破译 ASYN 水平的翻译后调节,这对于其稳态水平及其对神经元生理学的影响至关重要,以及它对蛋白质降解途径的影响,这可能对其致病作用至关重要。

项目成果

期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Abberant alpha-synuclein confers toxicity to neurons in part through inhibition of chaperone-mediated autophagy.
  • DOI:
    10.1371/journal.pone.0005515
  • 发表时间:
    2009
  • 期刊:
  • 影响因子:
    3.7
  • 作者:
    Xilouri M;Vogiatzi T;Vekrellis K;Park D;Stefanis L
  • 通讯作者:
    Stefanis L
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LEONIDAS STEFANIS其他文献

LEONIDAS STEFANIS的其他文献

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{{ truncateString('LEONIDAS STEFANIS', 18)}}的其他基金

alpha-synuclein and protein degradation
α-突触核蛋白和蛋白质降解
  • 批准号:
    7126109
  • 财政年份:
    2006
  • 资助金额:
    $ 11.8万
  • 项目类别:

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