MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
School of Biochemistry, University of Bristol, Biomedical Sciences Building, Bristol BS8 1TD, UK.
Philos Trans R Soc Lond B Biol Sci. 2024 Apr 8;379(1899):20220376. doi: 10.1098/rstb.2022.0376. Epub 2024 Feb 19.
While causative mutations in complex disorders are rare, they can be used to extract a biological pathway whose pathogenicity can generalize to common forms of the disease. Here we begin by relying on the biological consequences of mutations in LRRK2 and VPS35, genetic causes of autosomal-dominant Parkinson's disease, to hypothesize that 'Retromer-dependent lysosomal stress' represents a pathway that can generalize to idiopathic Parkinson's disease. Next, we outline a series of studies that can test this hypothesis, including the development of biomarkers of pathway dysfunction. If validated, the hypothesis can suggest a unified mechanism of disease and might inform future diagnostic and therapeutic investigations. This article is part of a discussion meeting issue 'Understanding the endo-lysosomal network in neurodegeneration'.
虽然复杂疾病中的因果突变很少见，但它们可以用来提取生物学途径，其致病性可以推广到疾病的常见形式。在这里，我们首先依赖于 LRRK2 和 VPS35 突变的生物学后果，这是常染色体显性帕金森病的遗传原因，假设“Retromer 依赖性溶酶体应激”代表一种可以推广到特发性帕金森病的途径。接下来，我们概述了一系列可以检验这一假设的研究，包括开发途径功能障碍的生物标志物。如果得到验证，该假说可以提出一种统一的疾病机制，并为未来的诊断和治疗研究提供信息。本文是“理解神经退行性疾病中的内溶酶体网络”讨论会议的一部分。
