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"Unifying disease mechanisms in hereditary spastic paraplegia"

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If you have a question about this talk, please contact Shannon Tinley-Browne.

Hereditary spastic paraplegias (HSPs) are genetic conditions characterised by distal axonal degenerations. Many of the genes mutated in HSP encode proteins involved in membrane traffic processes, with subsets involved in ER shaping, endosomal tubule fission and lysosomal function. No pathway unifying these seemingly distinct pathological subgroups has been identified. This talk focuses on the most commonly mutated HSP protein, spastin and its interactor IST1 . I will present our work showing that endosomal IST1 and an ER-localised isoform of spastin (M1-spastin) interact to define ER-endosome contacts that control endosomal tubule fission. Consequent defects in receptor sorting cause abnormal lysosomal enzyme traffic, resulting in abnormal lysosomal morphology, including in patient fibroblasts and neuronal cell models. Furthermore, we observed a similar lysosomal abnormality in cellular models of other HSPs associated with abnormal ER-shaping. As well as identifying a new role for ER-mediated endosomal tubule fission in controlling lysosomal function, by linking these processes we have identified a pathway that incorporates all classes of HSP proteins involved in membrane traffic. We propose this is the central pathway of HSP pathogenesis.

This talk is part of the BRC Seminar Series series.

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