Investigating lysosomal dysfunction as a unifying pathological mechanism in hereditary spastic paraplegia

研究溶酶体功能障碍作为遗传性痉挛性截瘫的统一病理机制

• 批准号: MR/R026440/1
• 负责人: Evan Reid
• 金额: $ 63.71万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR026440%2F1
• 关键词: Investigating; lysosomal; dysfunction; unifying; pathological

Hereditary spastic paraplegias (HSPs) are genetic conditions that cause progressive leg paralysis. They are currently untreatable, so it is critical that we understand the problems inside cells that are causing the condition, as this may suggest treatment options. The foundation for this project is our work linking the function of many HSP genes to a single vitalprocess. This work identified abnormalities in the lysosome (the cellular degradation and recycling centre) in several different genetic subtypes of HSP. Importantly, abnormal lysosomes were present in the nerve cells affected by HSP, where they accumulated in abnormal axonal swellings. Axons are the main cellular structures that degenerate to cause HSP; thus these abnormal lysosomes are directly located at the site of disease, making them prime candidates to be involved in its causation. The aim of our project is to understand the mechanisms by which these lysosomal problems could cause axonal degeneration, and to determine if improving lysosomal function could provide a treatment strategy for HSP.

遗传性痉挛性截瘫 (HSP) 是导致进行性腿部瘫痪的遗传性疾病。它们目前无法治疗，因此我们了解导致这种情况的细胞内部问题至关重要，因为这可能会建议治疗方案。该项目的基础是我们将许多 HSP 基因的功能与单个生命过程联系起来的工作。这项工作发现了几种不同 HSP 遗传亚型的溶酶体（细胞降解和回收中心）异常。重要的是，受 HSP 影响的神经细胞中存在异常溶酶体，它们在异常轴突肿胀中积累。轴突是退化引起HSP的主要细胞结构；因此，这些异常溶酶体直接位于疾病部位，使其成为参与疾病因果关系的主要候选者。我们项目的目的是了解这些溶酶体问题可能导致轴突变性的机制，并确定改善溶酶体功能是否可以为 HSP 提供治疗策略。

项目成果

AP-4 regulates neuronal lysosome composition, function, and transport via regulating export of critical lysosome receptor proteins at the trans-Golgi network.

• DOI: 10.1091/mbc.e21-09-0473
• 发表时间: 2022-10-01
• 期刊: MOLECULAR BIOLOGY OF THE CELL
• 影响因子: 3.3
• 作者: Majumder, Piyali;Edmison, Daisy;Rodger, Catherine;Patel, Sruchi;Reid, Evan;Gowrishankar, Swetha
• 通讯作者: Gowrishankar, Swetha