4.5 Article

Altered organization of the intermediate filament cytoskeleton and relocalization of proteostasis modulators in cells lacking the ataxia protein sacsin

Journal

HUMAN MOLECULAR GENETICS
Volume 26, Issue 16, Pages 3130-3143

Publisher

OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddx197

Keywords

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Funding

  1. Biotechnology and Biological Sciences Research Council (BBSRC) [BB/02294X/1]
  2. Canadian Institutes of Health Research (CIHR) Rare Disease Emerging Team
  3. Ataxia of Charlevoix-Saguenay Foundation
  4. Muscular Dystrophy Canada and Barts
  5. London Charity [417/1699, MGU0293]
  6. Barts [LSM880]
  7. Dementias and Neurodegenerative Diseases Research Network (DeNDRoN)
  8. Research Councils UK (RCUK)
  9. BBSRC [BB/L02294X/1] Funding Source: UKRI
  10. Barts Charity [MGU0293] Funding Source: researchfish
  11. Biotechnology and Biological Sciences Research Council [BB/L02294X/1] Funding Source: researchfish

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Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) is caused by mutations in the gene SACS, encoding the 520kDa protein sacsin. Although sacsin's physiological role is largely unknown, its sequence domains suggest a molecular chaperone or protein quality control function. Consequences of its loss include neurofilament network abnormalities, specifically accumulation and bundling of perikaryal and dendritic neurofilaments. To investigate if loss of sacsin affects intermediate filaments more generally, the distribution of vimentin was analysed in ARSACS patient fibroblasts and in cells where sacsin expression was reduced. Abnormal perinuclear accumulation of vimentin filaments, which sometimes had a cage-like appearance, occurred in sacsin-deficient cells. Mitochondria and other organelles were displaced to the periphery of vimentin accumulations. Reorganization of the vimentin network occurs in vitro under stress conditions, including when misfolded proteins accumulate. In ARSACS patient fibroblasts HSP70, ubiquitin and the autophagy-lysosome pathway proteins Lamp2 and p62 relocalized to the area of the vimentin accumulation. There was no overall increase in ubiquitinated proteins, suggesting the ubiquitin-proteasome system was not impaired. There was evidence for alterations in the autophagylysosome pathway. Specifically, in ARSACS HDFs cellular levels of Lamp2 were elevated while levels of p62, which is degraded in autophagy, were decreased. Moreover, autophagic flux was increased in ARSACS HDFs under starvation conditions. These data show that loss of sacsin effects the organization of intermediate filaments in multiple cell types, which impacts the cellular distribution of other organelles and influences autophagic activity.

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