Investigation of Heat shock Factor 1 as a Therapeutic Target for Huntington s Disease
Lead Research Organisation:
King's College London
Department Name: Genetics and Molecular Medicine
Abstract
Increased life expectancy in the developed world has resulted in a greater incidence of age-related neurodegenerative disorders such as Alzheimer?s disease and Parkinson?s disease, which already impose a significant health, social and economic burden on families, communities and the country as a whole. Insight into the cause of these diseases has arisen through the study of rare genetic forms of Alzheimer?s and Parkinson?s disease as well as from inherited disorders like Huntington?s disease. The underlying mutations cause disease related proteins to misfold and adopt abnormal shapes allowing them to interact with themselves or other proteins in a detrimental manner. These aberrant interactions result in the malfunction and death of brain cells. Treatments that will slow or halt the progression of these ?protein-folding? diseases do not exist.
All cells must ensure that as every protein is made, it is folded into the correct shape or conformation. Cells use ?chaperones? to fold proteins and if this is repeatedly unsuccessful, misfolded proteins are broken down or degraded. If this natural process to remove misfolded proteins becomes overwhelmed, as in the presence of a disease-related aggregation-prone protein, misfolded proteins accumulate and clump together as protein aggregates. The capacity of cells to maintain correctly folded proteins diminishes with age, resulting in an increasing susceptibility to protein-folding disease in the elderly.
Strategies that might decrease the propensity of an aggregation-prone protein to misfold include increasing either the protein folding or protein degradation capacity of the cell. One possible approach is to harness the cells? natural defence against insults that cause proteins to misfold e.g. heat or toxic chemicals. This ?heat shock response? leads to the immediate increase in levels of many chaperones known as heat shock proteins and is switched on by heat shock factor 1 (HSF1). We have recently gained access to a drug that can cross the blood brain barrier and activate HSF1 in brain cells. We are also generating mouse models in which we can induce the presence of an activated form of HSF1 in brain. We shall use these complementary approaches understand the heat shock response in brain cells and to test whether activation of HSF1 can alleviate disease-related phenotypes in a mouse model of Huntington?s disease. This work will allow us to determine whether the activation of HSF1 should be pursued as a target for therapeutic development for Huntington?s disease and other neurodegenerative disorders.
All cells must ensure that as every protein is made, it is folded into the correct shape or conformation. Cells use ?chaperones? to fold proteins and if this is repeatedly unsuccessful, misfolded proteins are broken down or degraded. If this natural process to remove misfolded proteins becomes overwhelmed, as in the presence of a disease-related aggregation-prone protein, misfolded proteins accumulate and clump together as protein aggregates. The capacity of cells to maintain correctly folded proteins diminishes with age, resulting in an increasing susceptibility to protein-folding disease in the elderly.
Strategies that might decrease the propensity of an aggregation-prone protein to misfold include increasing either the protein folding or protein degradation capacity of the cell. One possible approach is to harness the cells? natural defence against insults that cause proteins to misfold e.g. heat or toxic chemicals. This ?heat shock response? leads to the immediate increase in levels of many chaperones known as heat shock proteins and is switched on by heat shock factor 1 (HSF1). We have recently gained access to a drug that can cross the blood brain barrier and activate HSF1 in brain cells. We are also generating mouse models in which we can induce the presence of an activated form of HSF1 in brain. We shall use these complementary approaches understand the heat shock response in brain cells and to test whether activation of HSF1 can alleviate disease-related phenotypes in a mouse model of Huntington?s disease. This work will allow us to determine whether the activation of HSF1 should be pursued as a target for therapeutic development for Huntington?s disease and other neurodegenerative disorders.
Technical Summary
Within the aging populations of the developed world the health, social and economic burden of neurodegenerative disease is already substantial and expected to increase. The occurrence of the most common neurodegenerative disorders: Alzheimer?s disease (AD), Parkinson?s disease (PD) and amyotrophic lateral sclerosis (ALS) is largely sporadic, however, rare familial cases of these diseases, together with inherited monogenic disorders such as Huntington?s disease (HD) have provided clues to their aetiology. In AD, PD, ALS and HD, mutations result in the propensity of disease-associated proteins to misfold, form a-sheet structures and become ?aggregation-prone? properties for which they have been named ?protein-folding? diseases. In all cases, disease-modifying therapies do not exist.
All cells maintain protein-folding homeostasis through integrated protein-folding and clearance networks and pathways. Molecular chaperones direct the folding of newly synthesised and damaged proteins and those that cannot be successfully folded into their native conformation are degraded through the ubiquitin proteasome system (UPS) or cleared by lysosome-mediated autophagy. In the presence of an aggregation-prone protein, the mechanisms that maintain protein folding homeostasis become overwhelmed resulting in misfolding and aggregation. The capacity to maintain protein folding homeostasis diminishes with age, resulting in an increasing susceptibility to protein folding disease in the elderly.
Strategies that might decrease the propensity of an aggregation-prone protein to misfold include increasing either the protein folding or protein degradation capacity of the cell. One possible approach is to induce the cellular stress response. Conditions of cellular stress including elevated temperature and oxidative damage activate the heat shock response which results in the immediate induction of heat shock proteins that encode molecular chaperones and other proteins important for the recovery from stress induced protein damage. Heat shock factor 1 (HSF1) is the master regulator of the heat shock response and can be activated pharmacologically by inhibition of Hsp90. We shall use complimentary approaches: exposure to elevated temperature, administration of a brain penetrant Hsp90 inhibitor and the generation of mice expressing an inducible form of activated HSF1 to define the neuronal heat shock response in vivo and to determine whether activation of HSF1 can alleviate disease-related phenotypes in a mouse model of HD. Thereby, we shall validate whether HSF1 activation is a rational therapeutic target for HD, and by extension, other protein-folding neurodegenerative disorders.
All cells maintain protein-folding homeostasis through integrated protein-folding and clearance networks and pathways. Molecular chaperones direct the folding of newly synthesised and damaged proteins and those that cannot be successfully folded into their native conformation are degraded through the ubiquitin proteasome system (UPS) or cleared by lysosome-mediated autophagy. In the presence of an aggregation-prone protein, the mechanisms that maintain protein folding homeostasis become overwhelmed resulting in misfolding and aggregation. The capacity to maintain protein folding homeostasis diminishes with age, resulting in an increasing susceptibility to protein folding disease in the elderly.
Strategies that might decrease the propensity of an aggregation-prone protein to misfold include increasing either the protein folding or protein degradation capacity of the cell. One possible approach is to induce the cellular stress response. Conditions of cellular stress including elevated temperature and oxidative damage activate the heat shock response which results in the immediate induction of heat shock proteins that encode molecular chaperones and other proteins important for the recovery from stress induced protein damage. Heat shock factor 1 (HSF1) is the master regulator of the heat shock response and can be activated pharmacologically by inhibition of Hsp90. We shall use complimentary approaches: exposure to elevated temperature, administration of a brain penetrant Hsp90 inhibitor and the generation of mice expressing an inducible form of activated HSF1 to define the neuronal heat shock response in vivo and to determine whether activation of HSF1 can alleviate disease-related phenotypes in a mouse model of HD. Thereby, we shall validate whether HSF1 activation is a rational therapeutic target for HD, and by extension, other protein-folding neurodegenerative disorders.
Organisations
- King's College London, United Kingdom (Collaboration, Lead Research Organisation)
- University College London, United Kingdom (Collaboration)
- Washington University in St Louis, United States (Collaboration)
- Swiss Federal Institute of Technology in Lausanne (EPFL) (Collaboration)
- Mayo Foundation for Medical Education and Research (MFMER) (Collaboration)
- Massachusetts Institute of Technology (Collaboration)
- Merck (Collaboration)
- University of Auckland, New Zealand (Collaboration)
- University of Alabama at Birmingham, United States (Collaboration)
- Leiden University Medical Center (Collaboration)
- Novartis Institutes for Biomedical Research (NIBR) (Collaboration)
Publications

Carnemolla A
(2014)
Contesting the dogma of an age-related heat shock response impairment: implications for cardiac-specific age-related disorders.
in Human molecular genetics

Carnemolla A
(2015)
In Vivo Profiling Reveals a Competent Heat Shock Response in Adult Neurons: Implications for Neurodegenerative Disorders.
in PloS one

Labbadia J
(2011)
Altered chromatin architecture underlies progressive impairment of the heat shock response in mouse models of Huntington disease.
in The Journal of clinical investigation

Labbadia J
(2012)
Suppression of protein aggregation by chaperone modification of high molecular weight complexes.
in Brain : a journal of neurology

Landles C
(2010)
Proteolysis of mutant huntingtin produces an exon 1 fragment that accumulates as an aggregated protein in neuronal nuclei in Huntington disease.
in The Journal of biological chemistry

Neueder A
(2014)
Novel isoforms of heat shock transcription factor 1, HSF1?a and HSF1?ß, regulate chaperone protein gene transcription.
in The Journal of biological chemistry

Neueder A
(2017)
HSF1-dependent and -independent regulation of the mammalian in vivo heat shock response and its impairment in Huntington's disease mouse models.
in Scientific reports

Sathasivam K
(2010)
Identical oligomeric and fibrillar structures captured from the brains of R6/2 and knock-in mouse models of Huntington's disease.
in Human molecular genetics

Sathasivam K
(2013)
Aberrant splicing of HTT generates the pathogenic exon 1 protein in Huntington disease.
in Proceedings of the National Academy of Sciences of the United States of America
Description | EU JPND research initiative |
Geographic Reach | Asia |
Policy Influence Type | Membership of a guidance committee |
Impact | The Joint Programming Initiative in Neurodegeneration (JPND) has been established by 23 European countries to address the growing societal challenge presented by age-related neurodegeneration. This initiative spans the biomedical, healthcare and social science agendas, and seeks to improve the scientific understanding of neurodegenerative disorders, provide new approaches for their prevention, diagnosis and treatment, and ensure effective provision of health and social care and support, so that individuals can receive optimum care at all stages of their illness. |
Description | FP7 of the EU: networks for initial training |
Amount | £222,049 (GBP) |
Organisation | European Commission |
Department | Seventh Framework Programme (FP7) |
Sector | Public |
Country | European Union (EU) |
Start | 03/2011 |
End | 02/2015 |
Description | Joint Steering Committee grant - proteostasis |
Amount | £237,600 (GBP) |
Organisation | CHDI Foundation |
Sector | Charity/Non Profit |
Country | United States |
Start | 05/2016 |
End | 04/2020 |
Description | KCL travel bursary |
Amount | £500 (GBP) |
Organisation | King's College London |
Sector | Academic/University |
Country | United Kingdom |
Start |
Description | response mode funding |
Amount | £446,910 (GBP) |
Funding ID | MR/L003627/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 08/2013 |
End | 01/2017 |
Title | antibodies to HSF1 isoforms |
Description | antibodies to novel HSF1 isoforms |
Type Of Material | Technology assay or reagent |
Year Produced | 2014 |
Provided To Others? | Yes |
Impact | new isoforms of HSF1 have been confirmed at the protein level |
Title | HSP990 microarrays |
Description | gene expression analysis of brains from HD mouse models and controls with or without induction of HSF1 |
Type Of Material | Database/Collection of data |
Year Produced | 2011 |
Provided To Others? | Yes |
Impact | 126. Labbadia J, Cunliffe H, Weiss A, Katsyuba E, Sathasivam K, Seredenina T, Woodman B, Moussaoui S, Frentzel S, Luthi-Carter R, Paganetti P, Bates GP (2011) Altered chromatin architecture underlies progressive impairment of the heat shock response in Huntington's disease mice. J. Clin. Invest. 121, 3306-3319. |
Title | heat shock muscle RNA seq |
Description | RNA seq from muscle of WT and HD mice treated with HS or HSP990 |
Type Of Material | Database/Collection of data |
Year Produced | 2017 |
Provided To Others? | Yes |
Impact | None yet |
Description | DBC1 KO mice |
Organisation | Mayo Foundation for Medical Education and Research (MFMER) |
Country | United States |
Sector | Charity/Non Profit |
PI Contribution | Used the materials in novel research |
Collaborator Contribution | The collaborators provided us with well-characterised in vivo materials that we did not have to generate or characterise ourselves |
Impact | Tulino R, Benjamin AC, Jolinon N, Smith DL, Chini EN, Carnemolla A, Bates GP (2016) SIRT1 activity is linked to brain region specific phosphorylation and is impaired in Huntington's disease. PLoS ONE 11, e145425. |
Start Year | 2011 |
Description | FACS sorting |
Organisation | King's College London |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Use of facility for novel research |
Collaborator Contribution | provided access to and technical support for use of a FACS facility |
Impact | Carnemolla A, Lazell H, Moussaoui S, Bates GP (2015) In vivo profiling reveals a competent heat shock response in adult neurons: implications for neurodegenerative disorders. PLOS ONE 10, e0131985. |
Start Year | 2011 |
Description | Gensat mice |
Organisation | Merck |
Country | Germany |
Sector | Private |
PI Contribution | use of research materials for novel research |
Collaborator Contribution | The MMRRC provided access to four of the Gensat mouse lines. This saved us the cost of generating and characterising these lines ourselves |
Impact | Carnemolla A, Lazell H, Moussaoui S, Bates GP (2015) In vivo profiling reveals a competent heat shock response in adult neurons: implications for neurodegenerative disorders. PLOS ONE 10, e0131985. |
Start Year | 2010 |
Description | HD KI models |
Organisation | University of Alabama at Birmingham |
Department | Department of Biochemistry and Molecular Genetics |
Country | United States |
Sector | Academic/University |
PI Contribution | analysed mouse models in the publication below |
Collaborator Contribution | provided mouse models |
Impact | Sathasivam K*, Neueder A*, Gipson TA, Landles C, Benjamin AC, Bondulich MK, Smith DL, Faull RLM, Roos RAC, Howland D, Detloff PJ, Housman DE, Bates GP (2013). Aberrant splicing of HTT generates the pathogenic exon 1 protein in Huntington's disease. Proc. Natl. Acad. Sci. 110, 2366-2370. |
Start Year | 2010 |
Description | HD brain |
Organisation | University of Auckland |
Department | Anatomy with Radiology |
Country | New Zealand |
Sector | Academic/University |
PI Contribution | used post mortem brain material in publication below |
Collaborator Contribution | provided post mortem samples |
Impact | Sathasivam K*, Neueder A*, Gipson TA, Landles C, Benjamin AC, Bondulich MK, Smith DL, Faull RLM, Roos RAC, Howland D, Detloff PJ, Housman DE, Bates GP (2013). Aberrant splicing of HTT generates the pathogenic exon 1 protein in Huntington's disease. Proc. Natl. Acad. Sci. 110, 2366-2370. |
Start Year | 2011 |
Description | HD brain juvenile |
Organisation | Leiden University Medical Center |
Department | Department of Neurology |
Country | Netherlands |
Sector | Academic/University |
PI Contribution | analysed brain material in the publication below |
Collaborator Contribution | provided HD post mortem brain material |
Impact | Sathasivam K*, Neueder A*, Gipson TA, Landles C, Benjamin AC, Bondulich MK, Smith DL, Faull RLM, Roos RAC, Howland D, Detloff PJ, Housman DE, Bates GP (2013). Aberrant splicing of HTT generates the pathogenic exon 1 protein in Huntington's disease. Proc. Natl. Acad. Sci. 110, 2366-2370. |
Start Year | 2011 |
Description | HSJ1a mice |
Organisation | University College London |
Department | Institute of Ophthalmology UCL |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | performed a genetic cross between mice that are transgenic for the HSJ1a chaperone and a mouse model of HD. |
Collaborator Contribution | Supplied the HSJ1a transgenic mice and contributed to the analysis |
Impact | Labbadia J*, Novoselov SS*, Bett JS, Weiss A, Paganetti P, Bates GP#, Cheetham ME# (2012). Suppression of protein aggregation by chaperone modification of high molecular weight complexes. Brain 135, 1180-1196. |
Start Year | 2009 |
Description | HSP990 |
Organisation | Novartis Institutes for BioMedical Research (NIBR) |
Country | United States |
Sector | Private |
PI Contribution | used the reagent to generate the data in the publication below |
Collaborator Contribution | provided tool reagent |
Impact | Labbadia J, Cunliffe H, Weiss A, Katsyuba E, Sathasivam K, Seredenina T, Woodman B, Moussaoui S, Frentzel S, Luthi-Carter R, Paganetti P, Bates GP (2011) Altered chromatin architecture underlies progressive impairment of the heat shock response in Huntington's disease mice. J. Clin. Invest. 121, 3306-3319. Carnemolla A, Labbadia JP, Lazell H, Neueder A, Moussaoui S, Bates GP (2014) Contesting the dogma of an age-related heat shock response impairment; implications for cardiac-specific age-related disorders. Hum Mol Genet, 23, 3641-3656. Neueder A, Achilli F, Moussaoui S, Bates GP (2014) Novel isoforms of heat shock transcription factor 1, HSF1?a and HSF1?ß, regulate chaperone protein gene transcription. J Biol Chem, 289, 19894-19906. 159. Carnemolla A, Lazell H, Moussaoui S, Bates GP (2015) In vivo profiling reveals a competent heat shock response in adult neurons: implications for neurodegenerative disorders. PLOS ONE 10, e0131985. |
Start Year | 2009 |
Description | RNAseq |
Organisation | Massachusetts Institute of Technology |
Department | Department of Biology |
Country | United States |
Sector | Academic/University |
PI Contribution | Provided RNA from reagents generated in publication below |
Collaborator Contribution | Performed RNAseq on RNA supplied |
Impact | Sathasivam K*, Neueder A*, Gipson TA, Landles C, Benjamin AC, Bondulich MK, Smith DL, Faull RLM, Roos RAC, Howland D, Detloff PJ, Housman DE, Bates GP (2013). Aberrant splicing of HTT generates the pathogenic exon 1 protein in Huntington's disease. Proc. Natl. Acad. Sci. 110, 2366-2370. |
Start Year | 2011 |
Description | SIRT1 Transgenic mice |
Organisation | Washington University in St Louis |
Country | United States |
Sector | Academic/University |
PI Contribution | use of materials for novel research |
Collaborator Contribution | Generation and characterisation of a transgenic mouse model |
Impact | Tulino R, Benjamin AC, Jolinon N, Smith DL, Chini EN, Carnemolla A, Bates GP (2016) SIRT1 activity is linked to brain region specific phosphorylation and is impaired in Huntington's disease. PLoS ONE 11, e145425. |
Start Year | 2014 |
Description | chromatin immunoprecipitation |
Organisation | King's College London |
Department | School of Medicine KCL |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We were allowed access to equipment needed to prepare chromatin for immunoprecipitation |
Collaborator Contribution | providing us with access to equipment essential for experiments necessary for a publication |
Impact | The data that arose from this collaboratrion were published in Labbadia J (2011) J. Clin. Invest. 121, 3306-3319. |
Start Year | 2010 |
Description | microarrays |
Organisation | Swiss Federal Institute of Technology in Lausanne (EPFL) |
Country | Switzerland |
Sector | Public |
PI Contribution | provided RNA for microarray analysis from reagents generated in this grant |
Collaborator Contribution | performed expression microarrays on contractual basis |
Impact | Labbadia J, Cunliffe H, Weiss A, Katsyuba E, Sathasivam K, Seredenina T, Woodman B, Moussaoui S, Frentzel S, Luthi-Carter R, Paganetti P, Bates GP (2011) Altered chromatin architecture underlies progressive impairment of the heat shock response in Huntington's disease mice. J. Clin. Invest. 121, 3306-3319. |
Start Year | 2010 |
Description | Careers afternoon for graduate students |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Type Of Presentation | Workshop Facilitator |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Facilitated a careers afternoon for postgraduate students funded by the Neuromodel EU Marie Curie training netwrok Good feedback from the students about the presentations and the opportunity to discuss career options |
Year(s) Of Engagement Activity | 2012 |
Description | Headmasters annual conference |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Type Of Presentation | Keynote/Invited Speaker |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Headmasters experienced going back to school for a day. Gave a lesson to approx. 30 headmasters good feedback and request for transcript of presentation |
Year(s) Of Engagement Activity | 2013 |
Description | School visit (Brompton Oratory) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Type Of Presentation | Keynote/Invited Speaker |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | talk to and discussion with 6th formers about the ethics and implications of genetic research Very positive feedback, the school regretted not having made a video of the afternoon |
Year(s) Of Engagement Activity | 2011 |
Description | School visit (Guildford) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | Very engaged sixth formers invited speakers to discuss topics in which they were interested. the lecture continued as a careers discussion. |
Year(s) Of Engagement Activity | 2015 |
Description | UK HD netwrok |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Type Of Presentation | Keynote/Invited Speaker |
Geographic Reach | National |
Primary Audience | Health professionals |
Results and Impact | Approximately 100 health professional involved in the care of Huntinton's disease (physiotherapists, psychologists, social workers etc.) and lay group members Have been asked to address a psychiatric conference |
Year(s) Of Engagement Activity | 2011 |
Description | symposium at care home |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Type Of Presentation | Keynote/Invited Speaker |
Geographic Reach | National |
Primary Audience | Health professionals |
Results and Impact | talk given to ~ 80 GPs, carers, physiotherapists etc involved in the care of HD patients. Request to visit the research lab |
Year(s) Of Engagement Activity | 2013 |
Description | work experience for sixth formers |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | Arrangement with Tiffin Girls School for sixth form students to visit for work experience during the summer. Students from other schools take part on an ad hoc basis |
Year(s) Of Engagement Activity | 2006,2007,2008,2009,2010,2011,2012,2013,2014,2015,2016,2017,2018,2019 |