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Sacsin, the ARSACS disease protein, controls lysosomal positioning and reformation by regulating microtubule dynamics

ABSTRACT: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a fatal brain disorder featuring cerebellar neurodegeneration leading to spasticity and ataxia. ARSACS is caused by mutations in the SACS gene that encodes sacsin, a massive 4579 amino acid protein with multiple modular domains. Here we demonstrate that sacsin binds to microtubules and regulates microtubule dynamics. Loss of sacsin function in knockout cell lines, knockdown and knockout neurons, and patient fibroblasts leads to alterations in lysosomal transport, positioning, function and reformation following autophagy.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Fibroblast

SUBMITTER: Vincent Francis

LAB HEAD: Peter McPherson

PROVIDER: PXD033823 | Pride | 2022-10-15

REPOSITORIES: Pride

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The ARSACS disease protein sacsin controls lysosomal positioning and reformation by regulating microtubule dynamics.

Francis Vincent V Alshafie Walaa W Kumar Rahul R Girard Martine M Brais Bernard B McPherson Peter S PS

The Journal of biological chemistry 20220804 9

Autosomal recessive spastic ataxia of Charlevoix-Saguenay is a fatal brain disorder featuring cerebellar neurodegeneration leading to spasticity and ataxia. This disease is caused by mutations in the SACS gene that encodes sacsin, a massive 4579-amino acid protein with multiple modular domains. However, molecular details of the function of sacsin are not clear. Here, using live cell imaging and biochemistry, we demonstrate that sacsin binds to microtubules and regulates microtubule dynamics. Los ...[more]

PMID: 35933016

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