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Multi-omic profiling reveals the ataxia protein sacsin is required for integrin trafficking and synaptic organization

ABSTRACT: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a childhood-onset cerebellar ataxia caused by mutations in SACS, which encodes the protein sacsin. Cellular ARSACS phenotypes include mitochondrial dysfunction, intermediate filament disorganization, and the progressive death of cerebellar Purkinje neurons. It is unclear how the loss of sacsin function causes these deficits, or why they manifest as cerebellar ataxia. To investigate this, we performed multi-omic profiling of sacsin knockout cells and compared them to wild-type controls

ORGANISM(S): Homo sapiens

PROVIDER: GSE214213 | GEO | 2022/10/03

REPOSITORIES: GEO

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Project description:Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a childhood-onset cerebellar ataxia caused by mutations in SACS, which encodes the protein sacsin. Cellular ARSACS phenotypes include mitochondrial dysfunction, intermediate filament disorganization, and the progressive death of cerebellar Purkinje neurons. It is unclear how the loss of sacsin function causes these deficits, or why they manifest as cerebellar ataxia. Here, we performed multi-omic profiling in sacsin knockout (KO) cells, and identified alterations in microtubule dynamics, protein trafficking, and mislocalization of synaptic and focal adhesion proteins, including multiple integrins. Focal adhesion structure, signaling, and function were affected in KO cells, which could be rescued by reducing levels of PTEN, an overabundant negative regulator of focal adhesion signaling. Purkinje neurons in ARSACS mice possessed mislocalization of ITGA1, and disorganization of synaptic structures in the deep cerebellar nucleus (DCN). Interactome analysis revealed that sacsin regulates protein-protein interactions between structural and synaptic adhesion proteins. Our findings suggest that disrupted trafficking of synaptic adhesion proteins is a causal molecular deficit underlying ARSACS.

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