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Sacsin, mutated in the ataxia ARSACS, regulates intermediate filament assembly and dynamics.

FASEB J.2019 Feb;33(2):2982-2994. doi:10.1096/fj.201801556R. Epub 2018 Oct 17
Benoit J Gentil 1 , Gia-Thanh Lai 1 , Marie Menade 2 , Roxanne Larivière 3 , Sandra Minotti 4 , Kalle Gehring 2 , J-Paul Chapple 5 , Bernard Brais 3 , Heather D Durham 4
Benoit J Gentil 1 , Gia-Thanh Lai 1 , Marie Menade 2 , Roxanne Larivière 3 , Sandra Minotti 4 , Kalle Gehring 2 , J-Paul Chapple 5 , Bernard Brais 3 , Heather D Durham 4
+ et al

[No authors listed]

Author information
  • 1 Department of Kinesiology and Physical Education, McGill University, Montreal, Québec, Canada.
  • 2 Department of Biochemistry, Groupe de Recherche axé sur la Structure des Protéines, McGill University, Montreal, Québec, Canada.
  • 3 Laboratory of Neurogenetics of Motion, Montreal Neurological Institute, McGill University, Montreal, Québec, Canada; and.
  • 4 Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Québec, Canada.
  • 5 William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.

摘要

Loss of sacsin, a large 520 kDa multidomain protein, causes autosomal recessive spastic ataxia of the Charlevoix-Saguenay, one of the most common childhood-onset recessive ataxias. A prominent feature is abnormal bundling of neurofilaments in many neuronal populations. This study shows the direct involvement of sacsin domains in regulating intermediate filament assembly and dynamics and identifies important domains for alleviating neurofilament bundles in neurons lacking sacsin. Peptides encoding sacsin internal repeat (SIRPT) 1, J-domains, and ubiquitin-like domain modified neurofilament assembly in vivo. The domains with chaperone homology, the SIRPT and the J-domain, had opposite effects, promoting and preventing filament assembly, respectively. In cultured Sacs-/- motor neurons, both the SIRPT1 and J-domain resolved preexisting neurofilament bundles. Increasing expression of heat shock proteins also resolved neurofilament bundles, indicating that this endogenous chaperone system can compensate to some extent for sacsin deficiency.-Gentil, B. J., Lai, G.-T., Menade, M., Larivière, R., Minotti, S., Gehring, K., Chapple, J.-P., Brais, B., Durham, H. D. Sacsin, mutated in the ataxia ARSACS, regulates intermediate filament assembly and dynamics.

KEYWORDS: chaperone proteins, cytoskeleton, rare neurological diseases

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