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bioRxiv · 10.1101/2024.10.01.616079

CK1α, FAM83H, and FAM83B contribute to bundling of neurofilaments and are sequestered in cellular and mice models of ARSACS

Atkinson, C. S.·Cheng-Boivin, Z.·Larochelle, N.·Minotti, S.·Gentil, B. J.
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Abstract

Autosomal recessive spastic ataxia of the Charlevoix-Saguenay (ARSACS) is a rare neurodegenerative disorder characterized by mutations in the SACS gene that encodes for the sacsin protein. Sacsin dysfunction in ARSACS results in neurofilament bundling, a phenotype observed in various cellular models of ARSACS. The mechanisms underlying bundling in ARSACS remain unclear. With neurofilament phosphorylation controlling several processes of intermediate filament dynamics, its dysregulation may play a role in ARSACS. Accordingly, we investigated the interaction between CK1 (Casein Kinase 1) and its adaptor proteins FAM83H or FAM83B (FAMily with sequence similarity 83). Here, we report that these target proteins are upregulated in ARSACS patient fibroblasts and co-localize at the sites of intermediate filament bundling. In the Sacs-/- cerebellum, FAM83B compensated for the lack of FAM83H expression, suggesting a cell-type specific activity of CK1 that depends on the relative expression of its adaptor proteins. Further, CK1 inhibition with D4475 or knockdown of the target proteins with the CRISPR system caused neurofilament bundling, a phenotype that was only partially remedied by CK1 activation with SSTC3. Our findings suggest that CK1, FAM83H, and FAM83B contribute to neurofilament bundling in ARSACS; however, the inability of CK1 to resolve neurofilament bundling may reflect an error in a priming phosphorylation event in ARSACS. Future research is needed to understand the hierarchical phosphorylation cascade to CK1 activity and its contribution to ARSACS pathology. HighlightsO_LICK1 and its cell-specific adaptors are upregulated in ARSACS and targeted to the sites of bundles C_LIO_LIKnockdown of CK1, FAM83H, and FAM83B cause neurofilament bundling C_LIO_LIActivation of CK1 partially remediates bundling C_LI

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Atkinson, C. S., Cheng-Boivin, Z., Larochelle, N., Minotti, S., Gentil, B. J.. 2024-10-01. CK1α, FAM83H, and FAM83B contribute to bundling of neurofilaments and are sequestered in cellular and mice models of ARSACS. https://doi.org/10.1101/2024.10.01.616079

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