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

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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.