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Amplifying the Heat Shock Response Ameliorates ALS and FTD Pathology in Mouse and Human Models

Ahmed, Mhoriam; Spicer, Charlotte; Harley, Jasmine; Taylor, J Paul; Hanna, Michael; Patani, Rickie; Greensmith, Linda; (2023) Amplifying the Heat Shock Response Ameliorates ALS and FTD Pathology in Mouse and Human Models. Molecular Neurobiology 10.1007/s12035-023-03509-2. (In press). Green open access

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Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are now known as parts of a disease spectrum with common pathological features and genetic causes. However, as both conditions are clinically heterogeneous, patient groups may be phenotypically similar but pathogenically and genetically variable. Despite numerous clinical trials, there remains no effective therapy for these conditions, which, in part, may be due to challenges of therapy development in a heterogeneous patient population. Disruption to protein homeostasis is a key feature of different forms of ALS and FTD. Targeting the endogenous protein chaperone system, the heat shock response (HSR) may, therefore, be a potential therapeutic approach. We conducted a preclinical study of a known pharmacological amplifier of the HSR, called arimoclomol, in mice with a mutation in valosin-containing protein (VCP) which causes both ALS and FTD in patients. We demonstrate that amplification of the HSR ameliorates the ALS/FTD-like phenotype in the spinal cord and brain of mutant VCP mice and prevents neuronal loss, replicating our earlier findings in the SOD1 mouse model of ALS. Moreover, in human cell models, we demonstrate improvements in pathology upon arimoclomol treatment in mutant VCP patient fibroblasts and iPSC-derived motor neurons. Our findings suggest that targeting of the HSR may have therapeutic potential, not only in non-SOD1 ALS, but also for the treatment of FTD.

Type: Article
Title: Amplifying the Heat Shock Response Ameliorates ALS and FTD Pathology in Mouse and Human Models
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1007/s12035-023-03509-2
Publisher version: https://doi.org/10.1007/s12035-023-03509-2
Language: English
Additional information: © 2023 Springer Nature. This article is licensed under a Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/).
Keywords: ALS, Dementia, FTD, Heat shock response, Motor neuron, Proteostasis, Therapy, Treatment, VCP
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10174574
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