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Sacsin (SACS Protein)
Introduction
Sacsin (encoded by the [SACS gene](/genes/sacs)) is one of the largest human proteins (~520 kDa), functioning as a molecular chaperone critical for mitochondrial dynamics, protein quality control, and cytoskeletal organization in [neurons](/entities/neurons). Loss of sacsin causes ARSACS, a progressive neurodegenerative ataxia.
Overview
Sacsin is a 4,579-amino acid multidomain protein that integrates chaperone activity with mitochondrial regulation and cytoskeletal remodeling<sup>[1]</sup>. It is expressed at highest levels in cerebellar [Purkinje cells](/cell-types/purkinje-cells), consistent with the cerebellar-predominant neurodegeneration seen in ARSACS<sup>[2]</sup>. The protein contains several Hsp90-like sacsin repeating regions (SRRs) that confer ATPase-dependent chaperone function, along with a DnaJ domain for [Hsp70](/proteins/hsp70-protein) recruitment. [@anderson2010]
Sacsin contains a remarkable array of functional domains<sup>[1]</sup>:
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Sacsin (SACS Protein)
Introduction
Sacsin (encoded by the [SACS gene](/genes/sacs)) is one of the largest human proteins (~520 kDa), functioning as a molecular chaperone critical for mitochondrial dynamics, protein quality control, and cytoskeletal organization in [neurons](/entities/neurons). Loss of sacsin causes ARSACS, a progressive neurodegenerative ataxia.
Overview
Sacsin is a 4,579-amino acid multidomain protein that integrates chaperone activity with mitochondrial regulation and cytoskeletal remodeling<sup>[1]</sup>. It is expressed at highest levels in cerebellar [Purkinje cells](/cell-types/purkinje-cells), consistent with the cerebellar-predominant neurodegeneration seen in ARSACS<sup>[2]</sup>. The protein contains several Hsp90-like sacsin repeating regions (SRRs) that confer ATPase-dependent chaperone function, along with a DnaJ domain for [Hsp70](/proteins/hsp70-protein) recruitment. [@anderson2010]
[Engert JC et al., ARSACS, a spastic ataxia common in northeastern Quebec, is caused by mutations in a new gene encoding an 11.5-kb ORF (2000) (2000)](https://doi.org/10.1038/72167)
[Anderson JF et al., The sacsin repeating region (SRR): a novel Hsp90-related supra-domain associated with neurodegeneration (2010) (2010)](https://doi.org/10.1016/j.jmb.2010.08.009)
[Greer PL et al., Sacsin as a molecular chaperone for cytoskeletal and mitochondrial quality control (2018) (2018)](https://doi.org/10.1016/j.tcb.2018.02.006)
[Bradshaw TY et al., A reduction in Drp1-mediated fission compromises mitochondrial health in autosomal recessive spastic ataxia of Charlevoix Saguenay (2016) (2016)](https://doi.org/10.1093/hmg/ddw330)
[Duncan EJ et al., Altered organization of the intermediate filament cytoskeleton and relocalization of proteostasis modulators in cells lacking the ataxia protein sacsin (2017) (2017)](https://doi.org/10.1093/hmg/ddw408)
[Bouchard JP et al., Autosomal recessive spastic ataxia of Charlevoix-Saguenay (1998) (1998)](https://doi.org/10.1016/S0960-8966(97)