Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL, USA.
Departments of Neurology and Neurobiology, Center for Neurodegeneration and Experimental Therapeutics, Nathan Shock Center for Research on the Basic Biology of Aging, University of Alabama at Birmingham School of Medicine, Birmingham, AL, USA.
Hum Mol Genet. 2018 Dec 15;27(24):4176-4193. doi: 10.1093/hmg/ddy308.
Commonalities and, in some cases, pathological overlap between neurodegenerative diseases have led to speculation that targeting of underlying mechanisms might be of potentially shared therapeutic benefit. Alzheimer's disease is characterized by the formation of plaques, composed primarily of the amyloid-β 1-42 (Aβ) peptide in the brain, resulting in neurodegeneration. Previously, we have shown that overexpression of the lysosomal-trafficking protein, human Vps41 (hVps41), is neuroprotective in a transgenic worm model of Parkinson's disease, wherein progressive dopaminergic neurodegeneration is induced by α-synuclein overexpression. Here, we report the results of a systematic comparison of hVps41-mediated neuroprotection between α-synuclein and Aβ in transgenic nematode models of Caenorhabditis elegans. Our results indicate that an ARF-like GTPase gene product, ARL-8, mitigates endocytic Aβ neurodegeneration in a VPS-41-dependent manner, rather than through RAB-7 and AP3 as with α-synuclein. Furthermore, the neuroprotective effect of ARL-8 or hVps41 appears to be dependent on their colocalization and the activity of ARL-8. Additionally, we demonstrate that the LC3 orthologue, LGG-2, plays a critical role in Aβ toxicity with ARL-8. Further analysis of functional effectors of Aβ protein processing via the lysosomal pathway will assist in the elucidation of the underlying mechanism involving VPS-41-mediated neuroprotection. These results reveal functional distinctions in the intracellular management of neurotoxic proteins that serve to better inform the path for development of therapeutic interventions to halt neurodegeneration.
神经退行性疾病之间存在共同特征，在某些情况下还存在病理性重叠，这使得人们推测针对潜在机制的治疗可能具有潜在的共同治疗益处。阿尔茨海默病的特征是斑块的形成，这些斑块主要由大脑中的淀粉样β 1-42（Aβ）肽组成，导致神经退行性变。先前，我们已经表明，溶酶体运输蛋白人 Vps41（hVps41）的过表达在帕金森病的转基因蠕虫模型中具有神经保护作用，其中α-突触核蛋白的过表达诱导多巴胺能神经退行性变。在这里，我们报告了在秀丽隐杆线虫的转基因线虫模型中，hVps41 介导的α-突触核蛋白和 Aβ 之间的神经保护作用的系统比较结果。我们的结果表明，ARF 样 GTPase 基因产物 ARL-8 通过 VPS-41 依赖性而非通过 RAB-7 和 AP3 减轻内吞 Aβ 神经退行性变。此外，ARL-8 或 hVps41 的神经保护作用似乎依赖于它们的共定位和 ARL-8 的活性。此外，我们证明了 LC3 同源物 LGG-2 在 ARL-8 与 Aβ 毒性中起着关键作用。通过溶酶体途径对 Aβ 蛋白加工的功能效应器的进一步分析将有助于阐明涉及 VPS-41 介导的神经保护的潜在机制。这些结果揭示了神经毒性蛋白细胞内处理的功能区别，这有助于更好地阐明发展治疗干预措施以阻止神经退行性变的途径。
