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Amplifying the Heat Shock Response Ameliorates ALS and FTD Pathology in Mouse and Human Models
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 genet...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer US
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10657827/ https://www.ncbi.nlm.nih.gov/pubmed/37516663 http://dx.doi.org/10.1007/s12035-023-03509-2 |
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author | Ahmed, Mhoriam Spicer, Charlotte Harley, Jasmine Taylor, J. Paul Hanna, Michael Patani, Rickie Greensmith, Linda |
author_facet | Ahmed, Mhoriam Spicer, Charlotte Harley, Jasmine Taylor, J. Paul Hanna, Michael Patani, Rickie Greensmith, Linda |
author_sort | Ahmed, Mhoriam |
collection | PubMed |
description | 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12035-023-03509-2. |
format | Online Article Text |
id | pubmed-10657827 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Springer US |
record_format | MEDLINE/PubMed |
spelling | pubmed-106578272023-07-29 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 Mol Neurobiol Article 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12035-023-03509-2. Springer US 2023-07-29 2023 /pmc/articles/PMC10657827/ /pubmed/37516663 http://dx.doi.org/10.1007/s12035-023-03509-2 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Ahmed, Mhoriam Spicer, Charlotte Harley, Jasmine Taylor, J. Paul Hanna, Michael Patani, Rickie Greensmith, Linda Amplifying the Heat Shock Response Ameliorates ALS and FTD Pathology in Mouse and Human Models |
title | Amplifying the Heat Shock Response Ameliorates ALS and FTD Pathology in Mouse and Human Models |
title_full | Amplifying the Heat Shock Response Ameliorates ALS and FTD Pathology in Mouse and Human Models |
title_fullStr | Amplifying the Heat Shock Response Ameliorates ALS and FTD Pathology in Mouse and Human Models |
title_full_unstemmed | Amplifying the Heat Shock Response Ameliorates ALS and FTD Pathology in Mouse and Human Models |
title_short | Amplifying the Heat Shock Response Ameliorates ALS and FTD Pathology in Mouse and Human Models |
title_sort | amplifying the heat shock response ameliorates als and ftd pathology in mouse and human models |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10657827/ https://www.ncbi.nlm.nih.gov/pubmed/37516663 http://dx.doi.org/10.1007/s12035-023-03509-2 |
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