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

Autor:	Fernández Comaduran M; Department of Neurology & Neurosurgery and Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada., Minotti S; Department of Neurology & Neurosurgery and Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada., Jacob-Tomas S; Department of Biochemistry, McGill University, Montreal, Quebec, Canada., Rizwan J; Department of Biochemistry, McGill University, Montreal, Quebec, Canada., Larochelle N; Department of Neurology & Neurosurgery and Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada., Robitaille R; Département de Neurosciences and Groupe de Recherche sur le Système Nerveux Central, Université de Montréal, and Centre Interdisciplinaire de Recherche sur le Cerveau et l'apprentissage, Montreal, Quebec, Canada., Sephton CF; Department of Psychiatry and Neuroscience, CERVO Brain Research Centre, Laval University, Quebec City, Quebec, Canada., Vera M; Department of Biochemistry, McGill University, Montreal, Quebec, Canada., Nalbantoglu JN; Department of Neurology & Neurosurgery and Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada., Durham HD; Department of Neurology & Neurosurgery and Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada. Electronic address: heather.durham@mcgill.ca.
Jazyk:	angličtina
Zdroj:	Cell stress & chaperones [Cell Stress Chaperones] 2024 Jun; Vol. 29 (3), pp. 359-380. Date of Electronic Publication: 2024 Apr 01.
DOI:	10.1016/j.cstres.2024.03.010
Abstrakt:	Protein misfolding and mislocalization are common themes in neurodegenerative disorders, including motor neuron disease, and amyotrophic lateral sclerosis (ALS). Maintaining proteostasis is a crosscutting therapeutic target, including the 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 the expression of these HSPs in cultured motor neurons expressing three variants linked to familial ALS: TAR DNA binding protein 43 kDa (TDP-43) G348C , fused in sarcoma (FUS) R521G , or superoxide dismutase I (SOD1) G93A . 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 coinducer, arimoclomol, and class I histone deacetylase inhibitors, to promote active chromatin for transcription, and with the combination. Treatments had variable, often different effects on the 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 neuronal Brm/Brg-associated factor chromatin remodeling complex component Brg1, mitochondrial transport, FUS aggregation). Overall, histone deacetylase inhibition alone was effective on more measures than arimoclomol. As in the FUS model, arimoclomol failed to induce HSPA1A or preserve Hspa8 mRNA in the TDP-43 model, 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 Interests: Declarations of interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Heather D. Durham, Josephine N. Nalbantoglu, Chantelle F. Sephton, and Richard Robitaille report financial support was provided by Brain Canada and ALS Society of Canada. Mario Fernández Comaduran reports financial support was provided by Fonds de Recherche du Québec Nature et Technologies and Mitacs Globalink Graduate Fellowship, Consejo Nacional de Ciencia y Tecnología. Heather D. Durham reports equipment, drugs, or supplies were provided by BioMarin Pharmaceutical Inc. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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