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

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，因此我们必须了解导致这种情况的细胞内部问题，因为这可能会建议治疗方案。这个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。这项工作确定了HSP几种不同遗传亚型中溶酶体（细胞降解和再循环中心）的异常。重要的是，异常的溶酶体存在于HSP影响的神经细胞中，它们在异常的轴突中积聚。轴突是导致HSP退化的主要细胞结构;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为HSP提供治疗策略。

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.