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.

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.

Publications

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publication icon
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