We are analyzing https://link.springer.com/article/10.1007/s12035-023-03509-2.

Title:
Amplifying the Heat Shock Response Ameliorates ALS and FTD Pathology in Mouse and Human Models | Molecular Neurobiology
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.
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Keywords {🔍}

mvcp, mice, pubmed, arimoclomol, motor, article, google, scholar, brain, protein, neurons, hsr, tdp, ftd, fig, observed, cas, mouse, spinal, vcp, patients, cord, cell, cells, treatment, expression, hsp, patient, pathology, central, shock, heat, disease, human, study, stress, pathological, control, response, neuron, mutant, autophagy, sections, lateral, proteins, nuclear, muscle, wtvcp, number, aggregates,

Topics {✒️}

goat/donkey anti-rabbit/mouse alexa fluor 488 rickie patani & linda greensmith β-iii tubulin-labelled neuron hrp-conjugated secondary antibodies post-mortem brain tissue ipsc-derived motor neurons altering sqstm1/p62 phosphorylation c57bl/6j wildtype males article download pdf post-mortem brain samples primary antibody anti-hsp70 post-mortem brain cortex avidin-biotin conjugate layer reverts niemann-pick disease coordinating stress-induced transcription mvcp ipsc-derived neurons aaa+ protein vcp/p97 chaperone-mediated autophagy ubiquitin-positive inclusion bodies dna double-strand breaks niemann-pick disease type mvcp ipsc-motor neurons prevent sex differences confounding p62-positive protein aggregates ubiquitin-positive protein aggregates c57-black-6j mice prevent protein-protein interaction untreated mvcp ipsc-mns sod1-g93a mouse model motor neuron survival amyotrophic lateral sclerosis humidity-controlled environment maintained post-mortem brain subsequent gfap-labelling confirmed heat shock response age-matched control individuals motor neuron diseases heat shock factor-1 mvcp mouse spinal cord full size image tdp-43-positive cytoplasmic aggregation motor neuron area post hoc analysis motor neuron vulnerability heat shock protein motor neuron counts distinct neurodegenerative disorders derived motor neurons dapi-labelled fluorescent images additional secondary antibody

Schema {🗺️}

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         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.
         datePublished:2023-07-29T00:00:00Z
         dateModified:2023-07-29T00:00:00Z
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      headline:Amplifying the Heat Shock Response Ameliorates ALS and FTD Pathology in Mouse and Human Models
      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.
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      dateModified:2023-07-29T00:00:00Z
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         ALS
         FTD
         Dementia
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         Heat shock response
         Proteostasis
         Motor neuron
         Therapy
         Treatment
         Neurosciences
         Neurobiology
         Cell Biology
         Neurology
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               type:PostalAddress
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            address:
               name:The Francis Crick Institute, London, UK
               type:PostalAddress
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      name:Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK
      name:Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK
      name:The Francis Crick Institute, London, UK
      name:Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, USA
      name:Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK
      name:Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK
      name:The Francis Crick Institute, London, UK
      name:Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK

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