The role of ATP13A2/PARK9 in secretion of exosomes and alpha synuclein

神经退行性疾病的特征在于错误折叠的聚集的 神经元中的蛋白质。由于神经元是永久性的有丝分裂后，有效的细胞内蛋白 降解系统对于正常的神经元功能至关重要。最近的证据 表明溶酶体降解途径的破坏直接有助于 帕金森病和相关的突触核蛋白病的神经变性。我们先前已经 显示溶酶体ATP酶PARK 9（ATP 13 A2）的功能丧失导致锌 稳态异常、溶酶体功能障碍和α-syn积累。此外，我们和其他 发现PARK 9定位于多泡内体并调节外泌体生物发生。 在这里，我们建议进一步分析PARK 9在生成和分泌中的生理作用 以及PARK 9功能的丧失如何导致神经元功能障碍， 神经变性首先，我们将测试PARK 9在细胞中起重要作用的假设。 通过将锌依赖性FYVE蛋白募集到早期形成管腔内囊泡 核内体其次，我们将检查是否通过外泌体和溶酶体分泌α-syn。 胞吐作用有助于PARK 9介导的神经元功能障碍。最后，我们将测试 PARK 9通过在小鼠中过表达而在突触核蛋白病中具有保护性假说 积累α-突触核蛋白的模型。我们还将研究α-突触核蛋白在细胞中的增殖， PARK 9敲除和转基因小鼠。这些发现也将提供进一步的机制 对Kufor-Rakeb综合征背景下PARK 9功能丧失的见解以及更多 一般形式的syncleinopathies，如帕金森病（PD），特别是在细胞- 与这些疾病的发病机制有关的α-syn向细胞的传递。

Neurodegenerative disorders are characterized by the accumulation of misfolded aggregated proteins in neurons. Since neurons are permanently postmitotic, efficient intracellular protein degradation systems are critically important for normal neuronal function. Recent evidence suggests that disruption of lysosomal degradation pathways directly contributes to neurodegeneration in Parkinson's disease and related synucleinopathies. We have previously shown that loss of function of lysosomal ATPase PARK9 (ATP13A2) leads to zinc dyshomeostasis, lysosomal dysfunction and a-syn accumulation. In addition, we and other found that PARK9 localizes to multivesicular endosomes and regulates exosome biogenesis. Here, we propose to further analyze the physiological role of PARK9 in generation and secretion of exosomes and how loss of PARK9 function contributes to neuronal dysfunction and neurodegeneration. First, we will test the hypothesis that PARK9 plays an important role in the formation of intraluminal vesicles by recruitment of zinc-dependent FYVE proteins to early endosomes. Second, we will examine if a-syn secretion via exosomes and lysosomal exocytosis contributes to PARK9-mediated neuronal dysfunction. Finally, we will test the hypothesis that PARK9 is protective in synucleinopathies by overexpressing PARK9 in mouse models that accumulate a-synuclein. We will also examine propagation of a-synuclein in PARK9 knockout and transgenic mice. These findings will also provide further mechanistic insights into PARK9 loss of function in the context of Kufor-Rakeb syndrome as well as more general forms of syncleinopathies such as Parkinson's disease (PD), especially in terms of cell- to-cell transmission of a-syn that has been implicated in the pathogenesis of these disorders.