Biology subjects

Larochelle, N.

Publications and source records attributed to Larochelle, N..

2 recordsLinked to original sources

bioRxiv2024

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

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

cell biology↗

bioRxiv2023

Impact of histone deacetylase inhibition and arimoclomol on heat shock protein expression and disease biomarkers in primary culture models of familial ALS

Protein misfolding and mislocalization are common themes in neurodegenerative disorders, including the motor neuron disease, amyotrophic lateral sclerosis (ALS). Maintaining proteostasis is a crosscutting therapeutic target, including upregulation of heat shock proteins (HSP) to increase chaperoning capacity. Motor neurons have a high threshold for upregulating stress inducible HSPA1A, but constitutively express high levels of HSPA8. This study compared expression of these HSPs in cultured motor neurons expressing three variants linked to familial ALS: TDP-43G348C, FUSR521G or SOD1G93A. All variants were poor inducers of Hspa1a, and reduced levels of Hspa8 mRNA and protein, indicating multiple compromises in chaperoning capacity. To promote HSP expression, cultures were treated with the putative HSP co-inducer, arimoclomol, class I histone deacetylase (HDAC) inhibitors to promote active chromatin for transcription, and the combination. Treatments had variable, often different effects on expression of Hspa1a and Hspa8, depending on the ALS variant expressed, mRNA distribution (somata and dendrites), and biomarker of toxicity measured (histone acetylation, maintaining nuclear TDP-43 and the nBAF chromatin remodeling complex component Brg1, mitochondrial transport, FUS aggregation). Overall, HDAC inhibition alone was effective on more measures than arimoclomol. In the TDP-43 model, arimoclomol failed to induce HSPA1A or preserve Hspa8 mRNA, despite preserving nuclear TDP-43 and Brg1, indicating neuroprotective properties other than HSP induction. The data speak to the complexity of drug mechanisms against multiple biomarkers of ALS pathogenesis, as well as to the importance of HSPA8 for neuronal proteostasis in both somata and dendrites.

neuroscience↗