Investigation of the mechanism of CHMP2B-induced neurodegeneration using a novel transgenic mouse model

Lead Research Organisation: University College London
Department Name: Institute of Neurology

Abstract

The neurodegenerative diseases, which include Alzheimer's disease, Parkinson's disease, Huntington's disease, motor neuron disease and prion diseases cause huge social and economic burden. This burden is set to increase dramatically as the population ages. Currently no therapies are available for these diseases, implying an urgent need to better understand their causes and develop therapies. We have identified a new gene, termed CHMP2B, that causes an inherited form of dementia. We have shown that CHMP2B affects the ability of cells to break down proteins, which is a problem that has been identified in many other neurodegenerative diseases. We therefore plan to further investigate how CHMP2B affects brain cells as this should give insight into pathways that could be targeted therapeutically in many neurodegenerative diseases. However, a major challenge for developing therapies is understanding why brain cells are specifically affected, so that directed therapies without side effects can be developed. In order to understand how CHMP2B specifically affects brain cells, we have generated mice that model dementia caused by CHMP2B. These mice are a very powerful model as they mimic the processes occurring in human CHMP2B dementia brains. They will therefore allow us to specifically examine brain cells at very early stages of the disease in order to identify why they are particularly vulnerable to dysfunction and death. Identification of these pathways should give insight into brain cell vulnerability in other neurodegenerative diseases and could identify new avenues for treatments.

Technical Summary

The neurodegenerative diseases cause a devastating social and economic burden which will increase further as the population ages. No disease-modifying therapies are currently available, implying an urgent need to better understand neurodegenerative disease mechanisms in order to provide the foundation for therapeutic interventions. Mutations in the CHMP2B gene cause frontotemporal dementia, and affect two key cellular degradative pathways that converge on the lysosome: the endosome-lysosome pathway and autophagy. Both pathways have been implicated in a range of neurodegenerative diseases, suggesting that defining the mechanisms of CHMP2B-induced neurodegeneration will have broad impact for our understanding of neurodegenerative disease pathogenesis. However, how impairments in these central degradative pathways lead to selective neuronal dysfunction is unknown. This is a fundamental question as gaining insight into neuronal vulnerability is a key step for developing mechanism-based therapeutics. We have developed the first mouse model of CHMP2B-induced neurodegeneration, which recapitulates key aspects of human pathology. We will analyse endosomal and autophagic trafficking in primary neuronal cultures from these novel mice, in order to gain insight into the specific functions of these pathways that are required for neuronal survival. We will couple this analysis with state-of-the-art mass spectrometry to determine the specific proteins that accumulate due to impairments in these pathways. These insights should identify novel mechanisms that can be targeted therapeutically in a wide range of neurodegenerative diseases.

Planned Impact

The aim of this proposal is to generate new knowledge about the mechanisms that lead to neurodegenerative diseases.

This knowledge will benefit the biotech/pharmaceutical industry by providing new leads for the development of therapeutics for neurodegenerative diseases. They may also benefit from our training of highly skilled researchers with the opportunity to transfer their skills to the biotech/pharmaceutical or related industries.

Dementia patients will ultimately benefit from the development of drugs that can slow or halt their disease; this would directly contribute to improving the health and well-being of society. The development and commercialisation of a dementia therapy would also lead to huge economic benefit.

Publications

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Chassefeyre R (2015) Regulation of postsynaptic function by the dementia-related ESCRT-III subunit CHMP2B. in The Journal of neuroscience : the official journal of the Society for Neuroscience

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Lashley T (2013) RANTing about C9orf72. in Neuron

 
Description ARUK Pilot Project
Amount £30,891 (GBP)
Funding ID ARUK-PPG2014B-5 
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 12/2014 
End 03/2016
 
Description MRC Research Grant
Amount £40,849,849 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 03/2015 
End 04/2016
 
Title C9orf72 Drosophila models 
Description We developed novel Drosophila models of neurodegeneration caused by the C9orf72 repeat expansion, which is a common genetic cause of neurodegeneration. 
Type Of Material Model of mechanisms or symptoms - non-mammalian in vivo 
Year Produced 2014 
Provided To Others? Yes  
Impact Publication: Mizielinska S et al Science. 2014; 345:1192-1194. A large volume of requests for the Drosophila models from around the world 
 
Title C9orf72 RNA FISH + IF protocol 
Description We developed a novel RNA fluorescence in situ hybridisation (FISH) assay combined with protein immunofluorescence (IF) to identify and characterise new pathology in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) caused by C9orf72 mutation (the most common cause of FTD and ALS) . The technique is more sensitive than any previously reported and we are now providing it to the research community. 
Type Of Material Technology assay or reagent 
Year Produced 2013 
Provided To Others? Yes  
Impact Publication: Mizielinska S, Lashley T, Norona FE, Clayton EL, Ridler CE, Fratta P, Isaacs AM. C9orf72 frontotemporal lobar degeneration is characterised by frequent neuronal sense and antisense RNA foci. Acta Neuropathol. Epub Oct 2013. PMID:24170096. 
 
Title C9orf72 repeat DNA constructs 
Description We generated novel DNA constructs containing different versions and lengths of the C9orf72 repeat expansion that is a common cause of neurodegeneration. 
Type Of Material Model of mechanisms or symptoms - in vitro 
Year Produced 2014 
Provided To Others? Yes  
Impact Publication: Mizielinska S, et al C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins. Science. 2014; 345:1192-1194. Large volume of requests for the DNA constructs from around the world. 
 
Description FReJA consortium 
Organisation Lund University
Country Sweden 
Sector Academic/University 
PI Contribution Our group leads this consortium.
Collaborator Contribution Provision of samples and expertise
Impact 9 publications (PMIDs): 20223751, 19202337, 19150504, 18484988, 17917582, 22422914, 22786763, 23142962, 26358247. The FReJA consortium also engages in public engagement providing feedback to patients with CHMP2B mutations at regular meetings.
 
Description FReJA consortium 
Organisation University College London
Department Institute of Neurology
Country United Kingdom 
Sector Academic/University 
PI Contribution Our group leads this consortium.
Collaborator Contribution Provision of samples and expertise
Impact 9 publications (PMIDs): 20223751, 19202337, 19150504, 18484988, 17917582, 22422914, 22786763, 23142962, 26358247. The FReJA consortium also engages in public engagement providing feedback to patients with CHMP2B mutations at regular meetings.
 
Description FReJA consortium 
Organisation University College London
Department Institute of Neurology
Country United Kingdom 
Sector Academic/University 
PI Contribution Our group leads this consortium.
Collaborator Contribution Provision of samples and expertise
Impact 9 publications (PMIDs): 20223751, 19202337, 19150504, 18484988, 17917582, 22422914, 22786763, 23142962, 26358247. The FReJA consortium also engages in public engagement providing feedback to patients with CHMP2B mutations at regular meetings.
 
Description FReJA consortium 
Organisation University of Cambridge
Department School of Clinical Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Our group leads this consortium.
Collaborator Contribution Provision of samples and expertise
Impact 9 publications (PMIDs): 20223751, 19202337, 19150504, 18484988, 17917582, 22422914, 22786763, 23142962, 26358247. The FReJA consortium also engages in public engagement providing feedback to patients with CHMP2B mutations at regular meetings.
 
Description FReJA consortium 
Organisation University of Copenhagen
Country Denmark 
Sector Academic/University 
PI Contribution Our group leads this consortium.
Collaborator Contribution Provision of samples and expertise
Impact 9 publications (PMIDs): 20223751, 19202337, 19150504, 18484988, 17917582, 22422914, 22786763, 23142962, 26358247. The FReJA consortium also engages in public engagement providing feedback to patients with CHMP2B mutations at regular meetings.
 
Description Ionis 
Organisation Ionis Pharmaceuticals
Country United States 
Sector Private 
PI Contribution We tested antisense oligonucleotides developed by Ionis Pharmaceuticals in neurons with an FTD-causing CHMP2B mutation.
Collaborator Contribution Ionis Pharmaceuticals provided specifc antisense oligonucleotides
Impact One publication: Clayton EL, Norona FE, Edgar JR, Milioto C, Soriano A, Jafar-nejad P, Rigo F, Collinge J, Isaacs AM. Frontotemporal dementia causing CHMP2B impairs endolysosomal traffic - rescue by TMEM106B antisense oligonucleotides. Brain. 2018 Dec 1;141(12):3428-3442.
Start Year 2015
 
Description Ada Lovelace Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Schools
Results and Impact Talks and research demonstration led to many thoughtful questions and discussion.

Visit by female GCSE pupils who stated they were more likely to try to get a job in science.
Year(s) Of Engagement Activity 2015
 
Description FTDtalk 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Patients, carers and/or patient groups
Results and Impact We developed a website and twitter and facerbook resource called FTDtalk, for patients, carers and the wider public to enable greater understanding of frontotemporal dementia. The website gets 3000-4000 visits per month and positive feedback from users.
Year(s) Of Engagement Activity 2014,2015,2016
URL http://www.ftdtalk.org/
 
Description Patient Feedback (Denmark) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Participants in your research and patient groups
Results and Impact An update on research findings was provided to approximately 40 family members with inherited dementia. This sparked discussion regarding genetic testing for the condition and volunteering for blood donation.

31 family members donated blood for research.
Year(s) Of Engagement Activity 2010,2015
 
Description Patient support group 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact The UCL Dementia Research Center hosts an annual support day for patients and careers with familial frontotemporal dementia. I gave a talk about my research and also stayed for the day which enabled further one-on-one discussions.
Year(s) Of Engagement Activity 2015
 
Description Press release (Science paper) 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Our research was reported by 5 news outlets

Media activity about our paper led to an Altmetric score of 91.
Year(s) Of Engagement Activity 2014
 
Description Web news article (Science paper) 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact The Motor Neurone Disease Association wrote an article for their website about our paper published in Science, linked to a more detailed blog post. Usage statistics were: the announcement of the website and blog reached 10,300 Facebook users and 1023 twitter feeds; the website news piece had 1010 views; the blog article had 1146 views.

998 Facebook users engaged with the blog and news story: 289 users were talking about the feature; 225 users 'liked' the post; 76 users 'shared' the post to their Facebook friends; 34 people commented on the post (highlighting that it's a great development which they hope can lead to new understandings and treatments in the future).
Year(s) Of Engagement Activity 2012,2014