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Sacsin Deletion Induces Aggregation of Glial Intermediate Filaments

Authors :
Fernanda Murtinheira
Mafalda Migueis
Ricardo Letra-Vilela
Mickael Diallo
Andrea Quezada
Cláudia A. Valente
Abel Oliva
Carmen Rodriguez
Vanesa Martin
Federico Herrera
Source :
Cells, Vol 11, Iss 2, p 299 (2022)
Publication Year :
2022
Publisher :
MDPI AG, 2022.

Abstract

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disorder commonly diagnosed in infants and characterized by progressive cerebellar ataxia, spasticity, motor sensory neuropathy and axonal demyelination. ARSACS is caused by mutations in the SACS gene that lead to truncated or defective forms of the 520 kDa multidomain protein, sacsin. Sacsin function is exclusively studied on neuronal cells, where it regulates mitochondrial network organization and facilitates the normal polymerization of neuronal intermediate filaments (i.e., neurofilaments and vimentin). Here, we show that sacsin is also highly expressed in astrocytes, C6 rat glioma cells and N9 mouse microglia. Sacsin knockout in C6 cells (C6Sacs−/−) induced the accumulation of the glial intermediate filaments glial fibrillary acidic protein (GFAP), nestin and vimentin in the juxtanuclear area, and a concomitant depletion of mitochondria. C6Sacs−/− cells showed impaired responses to oxidative challenges (Rotenone) and inflammatory stimuli (Interleukin-6). GFAP aggregation is also associated with other neurodegenerative conditions diagnosed in infants, such as Alexander disease or Giant Axonal Neuropathy. Our results, and the similarities between these disorders, reinforce the possible connection between ARSACS and intermediate filament-associated diseases and point to a potential role of glia in ARSACS pathology.

Details

Language :
English
ISSN :
20734409
Volume :
11
Issue :
2
Database :
Directory of Open Access Journals
Journal :
Cells
Publication Type :
Academic Journal
Accession number :
edsdoj.6fd608b093224589afbfc1a1550049a4
Document Type :
article
Full Text :
https://doi.org/10.3390/cells11020299