Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI 49503, USA.
Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI 49503, USA.
Neurobiol Dis. 2022 Aug;170:105768. doi: 10.1016/j.nbd.2022.105768. Epub 2022 May 16.
Perturbations of the endolysosomal pathway have been suggested to play an important role in the pathogenesis of several neurodegenerative diseases, including Parkinson's disease (PD) and Alzheimer's disease (AD). Specifically, VPS35 and the retromer complex play an important role in the endolysosomal system and are implicated in the pathophysiology of these diseases. A single missense mutation in VPS35, Asp620Asn (D620N), is known to cause late-onset, autosomal dominant familial PD. In this review, we focus on the emerging role of the PD-linked D620N mutation in causing retromer dysfunction and dissect its implications in neurodegeneration. Additionally, we will discuss how VPS35 and the retromer are linked to AD, amyotrophic lateral sclerosis, and primary tauopathies. Interestingly, reduced levels of VPS35 and other retromer components have been observed in post-mortem brain tissue, suggesting a role for the retromer in the pathophysiology of these diseases. This review will provide a comprehensive dive into the mechanisms of VPS35 dysfunction in neurodegenerative diseases. Furthermore, we will highlight outstanding questions in the field and the retromer as a therapeutic target for neurodegenerative disease at large.
内溶酶体途径的扰动被认为在几种神经退行性疾病的发病机制中起着重要作用，包括帕金森病（PD）和阿尔茨海默病（AD）。具体来说，VPS35 和逆行转运体复合物在内溶酶体系统中起着重要作用，并与这些疾病的病理生理学有关。VPS35 中的单个错义突变，天冬氨酸 620 到天冬酰胺（D620N），已知会导致迟发性、常染色体显性家族性 PD。在这篇综述中，我们重点关注与 PD 相关的 D620N 突变导致逆行转运体功能障碍的新作用，并剖析其在神经退行性变中的意义。此外，我们将讨论 VPS35 和逆行转运体如何与 AD、肌萎缩侧索硬化和原发性 tau 病相关。有趣的是，在死后脑组织中观察到 VPS35 和其他逆行转运体成分的水平降低，这表明逆行转运体在这些疾病的病理生理学中起作用。这篇综述将全面探讨 VPS35 功能障碍在神经退行性疾病中的机制。此外，我们将强调该领域的悬而未决的问题以及逆行转运体作为神经退行性疾病的治疗靶点。
