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

• Published in: bioRxiv
• Main Authors: Mario Fernandez Comaduran, Minotti, Sandra, Jacob-Tomas, Suleima, Javeria Rizwan, Larochelle, Nancy, Robitaille, Richard, Sephton, Chantelle F, Vera, Maria, Nalbantoglu, Josephine N, Durham, Heather D
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 14.12.2023
• Subjects: Acetylation; Amyotrophic lateral sclerosis; Biomarkers; BRG1 protein; Chromatin remodeling; Dendrites; Heat shock proteins; Histone deacetylase; Motor neuron diseases; Neurodegenerative diseases; Neuroprotection; Protein folding; Therapeutic targets; Toxicity
• DOI: 10.1101/2023.12.13.571549

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.Competing Interest StatementThe authors have declared no competing interest.