Tackling autophagy and apoptosis for the potential therapy of Huntington's Disease

Lead Research Organisation: University of Plymouth
Department Name: Peninsula Medical School

Abstract

Huntington's Disease (HD) is a devastating dementia disease. The alteration in a gene called huntingtin (htt) leads to changed Htt protein and its toxic aggregates, which in turn cause brain cell death and HD. Strong evidence has shown that cellular "self-eating "process, termed autophagy, counteracts dementia diseases such as HD because autophagy clears up protein aggregates in cells, thereby removing their toxicity to cells. Defects in autophagy give rise to various dementia diseases.

Bim is a critical protein that causes cell death in various tissues including those in brains. Recently we found that Bim also suppresses autophagy in addition to its cell death induction. Therefore, Bim are involved in autophagy inhibition and cell death induction, both of which are relevant to HD. Previously, Bim was shown to be increased in HD models, and we observed that reduction of Bim decreased toxic Htt protein aggregates and cell death in HD cells. These suggest that Bim may be an important driver for HD progression. Importantly, we identified a portion of Bim (Bim-P) capable of enhancing autophagy and reducing toxic Htt protein aggregates in HD cells. Based on the preliminary data, we will further establish the process that causes the increase of Bim protein in HD, examine if Bim contributes to HD progression and test the efficacy of Bim-P in treating HD using HD mouse models.

Technical Summary

Huntingtin's Disease (HD) is a progressive neurodegenerative disorder, caused by mutant huntingtin gene (htt) with expanded CAG repeats, which are translated into expanded polyglutamine (polyQ) stretch. The expanded polyQ forms toxic aggregates that induce neuronal death. It has been well characterised that mutant Htt (mHtt) aggregates can be degraded by autophagy, a lysosome-dependent bulk degradation system, and autophagy upregulation ameliorates HD and other neurodegenerative diseases.

Autophagy consists of autophagosome synthesis (cargo delivery) and autophagosome-lysosome fusion (cargo degradation). The initiation of autophagosome synthesis is tightly regulated by a set of autophagy genes, such as Atg1, Beclin 1 and class III PI-3 kinase Vps34. The Beclin 1-Vps34 localisation at ER is critical for the formation of autophagosomes. We found that pro-apoptotic protein Bim restricts Beclin 1-Vps34 complex to microtubules away from its functional site ER, thereby suppressing autophagy. Bim is therefore a dual regulator that promotes apoptosis but inhibits autophagy.

Our preliminary data show that the protein and mRNA levels of Bim were significantly enhanced in human HD post-mortem striatum, confirming previous data that Bim levels are increased in HD mouse and cell models. Collectively, these suggest that Bim may a driving factor to progression of HD pathology. We observed that depletion of Bim with RNA interference significantly reduced mutant Htt aggregation and toxicity in cells. Importantly, a peptide derived from Bim (Bim-P) promotes autophagy by antagonising Bim's autophagy inhibition, and reduces mutant Htt aggregation and toxicity in HD in vitro.

Based on the preliminary data, we will establish the mechanism by which Bim is upregulated in HD, examine the effect of Bim in HD progression in vivo using HD mouse models and test the efficacy of the Bim-P in treating the HD mouse models.

Planned Impact

Subjects related to autophagy and cell death are rapidly developing. The relevant research breakthrough has been published in high-impact journals and made headlines in mass media. Whilst significant progress has been made, many more mysteries need to solve so that diseases can be better treated through knowledge. This project will generate such important scientific data, advancing our knowledge in the pathogenesis and therapy of Huntington's Disease (HD) as well as other neurodegenerative diseases. Importantly, this research area is underrepresented in UK at the time being, and our study will significantly contribute to UK's leading position in the field.

Neurodegenerative diseases, such as Huntington's Disease, Alzheimer's Disease and Parkinson's Disease, have tremendous influence on our lives in 21st century. Autophagy and apoptosis are closely linked with these diseases. This study will benefit patients by investigating the potential role of Bim as a driving factor to HD progression and testing the efficacy of a therapeutic agent in treating HD.

The proposed project will be a platform to train a post-doctoral scientist. He/she will have opportunities to gain or improve a wide range of knowledge and expertise in biochemistry, molecular and cellular biology and genetics. The training will be essential for professional scientists to work in either academia or industry. In addition, this project will be in connection with undergraduate and graduate students in Plymouth University Peninsula Schools of Medicine and Dentistry (PUPSMD) so that they can get involved in basic lab training, which will be important for them to explore their interests in scientific research in the future.

This study will generate world-class basic and drug-discovery study in HD and will significantly contribute to strengthening the reputation of PUPSMD. This project has potential to be translated into bedside medicine, and we will closely interact with a number of existing groups in PUPSMD who are working in translational medicine, and actively exchange ideas in the relevant areas, such as drug development and clinical trial.

Publications

10 25 50
 
Description A novel autophagy pathway
Amount £78,877 (GBP)
Organisation University of Plymouth 
Sector Academic/University
Country United Kingdom
Start 01/2017 
End 12/2019
 
Description Does lowering futile autopohagosome synthesis alleviate aggregation-prone protein toxicity in dementia diseases?
Amount £58,545 (GBP)
Organisation BRACE (Alzheimer's disease charity) 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2017 
End 08/2018
 
Description Living with Huntington's disease
Amount £10,000 (GBP)
Organisation Hospital Saturday Fund 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2017 
End 01/2018
 
Description Mechanisms of mitochondrial dynamics dysfunction in dementia diseases
Amount £85,863 (GBP)
Organisation BRACE (Alzheimer's disease charity) 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2018 
End 09/2021
 
Description Collaboration with Professor Boxun Lu 
Organisation Fudan University
Country China 
Sector Academic/University 
PI Contribution I have been co-supervising the researchers in Prof Lu's lab to conduct autophagy assays and mutant huntingtin toxicity in the work.
Collaborator Contribution Prof Lu has been supervising the researchers in his lab for the project.
Impact The project results in the paper " Suppression of MAPK11 or HIPK3 reduces mutant Huntingtin levels in Huntington's disease models", which has been published in Cell Research. The collaboration is not multi-disciplinary.
Start Year 2017
 
Description TheBEACH-containing protein WDR81 coordinates p62 and LC3C to promote aggrephagy 
Organisation Chinese Academy of Sciences
Department Institute of Genetics & Developmental Biology
Country China 
Sector Academic/University 
PI Contribution I was awarded a collaborative grant with Prof Yang from National Natural and Science Foundation of China for the project to be carried out in Prof Yang's laboratory, and have been co-supervising a researcher in Prof Yang's lab for this work.
Collaborator Contribution Prof Yang has been supervising the researchers in his lab for the project.
Impact The project results in the paper "TheBEACH-containing protein WDR81 coordinates p62 and LC3C to promote aggrephagy", which has been accepted by the Journal of Cell Biology The collaboration is not multi-disciplinary.
Start Year 2016
 
Description A-level students experienced research in my lab 
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 A-level students experienced research in my lab
Year(s) Of Engagement Activity 2017
 
Description BBC Devon Spotlight interview 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Introduced our Huntington Disease research to the local public to generate awareness for the disease.
Year(s) Of Engagement Activity Pre-2006,2006
 
Description Local HD patients and relatives' lab visit 
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 Patients, carers and/or patient groups
Results and Impact 30 local Huntington Disease patients and relatives visited the lab for better understanding the disease, current research progress and the prospect of therapy, generating wide awareness to the disease and its research.
Year(s) Of Engagement Activity 2006,2016
 
Description Radio BBC Cornwall interview 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Introduced Huntington Disease and our research to local public for the awareness of the public to the disease and its related research.
Year(s) Of Engagement Activity 2007
 
Description Strategies to fight against neurodegenerative diseases (Swindon) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact about 100 researchers and doctors attended for the workshop to communicate the research updates in the area of neurodegeneration.
Year(s) Of Engagement Activity 2016
 
Description Undergraduate students from Bath University experienced HD research in my lab 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Undergraduate students
Results and Impact Undergraduate students from Bath University experienced HD research in my lab.
Year(s) Of Engagement Activity 2014,2015,2016,2017
 
Description the London PhD Network (LPN) 5th Symposium 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact Engaged in the London PhD Network (LPN) 5th Symposium: Neuroscience and CRYO-EM, where I was an organiser and speaker
Year(s) Of Engagement Activity 2017