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

遗传性痉挛性截瘫（HSPs）是一种导致进行性腿部瘫痪的遗传性疾病。它们目前是无法治愈的，所以我们了解导致这种情况的细胞内部问题是至关重要的，因为这可能会提供治疗方案。这个项目的基础是我们将许多热休克蛋白基因的功能与一个单一的重要过程联系起来。这项工作确定了几种不同遗传亚型HSP中溶酶体（细胞降解和再循环中心）的异常。重要的是，受热休克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聚。轴突是退化引起热休克的主要细胞结构；因此，这些异常溶酶体直接位于疾病的部位，使它们成为其病因的主要候选者。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提供治疗热休克的策略。

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.