The J Domain of Sacsin Disrupts Intermediate Filament Assembly

Autosomal Recessive Spastic Ataxia of the Charlevoix Saguenay (ARSACS) is caused by mutation in the SACS gene resulting in loss of function of the protein sacsin. A key feature is the formation of abnormal bundles of neurofilaments (NF) in neurons and vimentin intermediate filaments (IF) in cultured...

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Bibliographic Details
Published in:International journal of molecular sciences 2022-12, Vol.23 (24), p.15742
Main Authors: Dabbaghizadeh, Afrooz, Paré, Alexandre, Cheng-Boivin, Zacharie, Dagher, Robin, Minotti, Sandra, Dicaire, Marie-Josée, Brais, Bernard, Young, Jason C, Durham, Heather D, Gentil, Benoit J
Format: Article
Language:English
Subjects:
Ataxia
Autophagy
chaperone
Dismantling
Fibroblasts
Filaments
Heat shock proteins
Heat-Shock Proteins - metabolism
Homeostasis
Hsp40 protein
Hsp70 protein
Humans
Intermediate filaments
Intermediate Filaments - metabolism
J domain
motor neuron
Motor neurons
Motor Neurons - metabolism
Muscle Spasticity - genetics
Muscle Spasticity - metabolism
Mutation
Myc protein
neurofilament
Neurofilaments
Neurons
Patients
Peptides
Proteins
Quality control
Sedimentation & deposition
Vimentin
Vimentin - genetics
Vimentin - metabolism
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Summary:Autosomal Recessive Spastic Ataxia of the Charlevoix Saguenay (ARSACS) is caused by mutation in the SACS gene resulting in loss of function of the protein sacsin. A key feature is the formation of abnormal bundles of neurofilaments (NF) in neurons and vimentin intermediate filaments (IF) in cultured fibroblasts, suggesting a role of sacsin in IF homeostasis. Sacsin contains a J domain (SacsJ) homologous to Hsp40, that can interact with Hsp70 chaperones. The SacsJ domain resolved NF bundles in cultured neurons. Having studied the mechanism using NF assembled in vitro from purified NF proteins, we report that the SacsJ domain interacts with NF proteins to disassemble NFL filaments, and to inhibit their initial assembly. A cell-penetrating peptide derived from this domain, SacsJ-myc-TAT was efficient in disassembling NF bundles in cultured motor neurons, restoring the NF network; however, there was some loss of vimentin IF and NF in cultured fibroblasts and motor neurons, respectively. These results suggest that sacsin through its SacsJ domain is a key regulator of NF and vimentin IF networks in cells.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms232415742