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

Abstract

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., Chappie, J.‐P., Brais, B., Durham, H. D. Sacsin, mutated in the ataxia ARSACS, regulates intermediate filament assembly and dynamics. FASEB J. 33, 2982–2994 (2019). http://www.fasebj.org

Rewiring of the Human Mitochondrial Interactome during Neuronal Reprogramming Reveals Regulators of the Respirasome and Neurogenesis

“…As for marker genes from immunoblotting or RNA-seq for ECSCs and DNLCs (Figures 1B and 1C), the overall average expression level of single cells correlated well ( r = 0.8) with the bulk cell populations (Figure 1F). An illustrative example is the involvement of an ARSACS (autosomal recessive spastic ataxia of Charlevoix-Saguenay)-causing SACS gene in the regulation of class III ( PRPH ) and IV ( NF-L/M/H ; INA ) intermediate filament genes expressed in neurons (Gentil et al., 2019). Consistent with this observation, bulk RNA-seq and scRNA-seq showed an increased expression of classes III and IV genes in DNLCs, except SACS and INA , which exhibited decreased expression (Figure 1F), revealing a cell type-specific outcome.…”

Case Report: Expanding the Genetic and Phenotypic Spectrum of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay

“…(Parfitt et al, 2009). Recent evidence indicates that SACS domains regulate intermediate filament assembly (Gentil et al, 2019). SACS-knockout mice have also been shown to exhibit early ataxia and abnormal bundling of neurofilaments in different neuronal populations (Lariviere et al, 2015).…”

Homeostatic Roles of the Proteostasis Network in Dendrites

“…Finally, sacsin, an enormous 520 kDa protein, has just been classified in the past decade as a chaperone because of its Hsp90 and DNAJ (Hsp40)-like domains which may function as chaperone and co-chaperone, respectively (Anderson et al, 2011). Sacsin is required for proper organization of neurofilaments in several types of neurons, including Purkinje and pyramidal neurons, and when mutated -as in the case of the hereditary disorder autosomal recessive spastic ataxia of the Charlevoix-Saguenay -leads to abnormal somatodendritic bundles of neurofilaments (Gentil et al, 2019;Larivière et al, 2019). The localization and mutation studies clearly indicate an important role of chaperones in forming and maintaining dendritic arbors.…”

“…For example, in a genetic screen of mutations associated with schizophrenia and ASD, 16% of the genes screened were found to be required for proper dendritic morphology in C. elegans ( Aguirre-Chen et al, 2020 ). Additionally, though the symptoms of autosomal recessive spastic ataxia of the Charlevoix-Saguenay are mainly due to axonal deformities, the underlying mutation of the sacsin chaperone also results in neurofilament bundling in dendrites ( Anderson et al, 2011 ; Gentil et al, 2019 ; Larivière et al, 2019 ). The effects of dendritic arborization deficits in these rare diseases may have been previously overshadowed by the dramatic axonal effects, and should be examined in future studies.…”