Molecular Investigations of Frontotemporal Lobar Degeneration

Lead Research Organisation: University of Manchester
Department Name: Medical and Human Sciences

Abstract

Approximately 750,000 people in the UK have dementia, the most common and widely known is Alzheimer‘s disease. The second most common form of dementia is called frontotemporal lobar degeneration (FTLD). We know around 5% of cases of FTLD are caused by errors in a gene called tau and another 5% is caused by errors in a gene called progranulin. There is an unknown gene on chromosome 9 that can cause FTLD and motor neuron disease. We believe we have now identified this gene (called UBAP1) and experiments we have done suggest it maybe important in regulating the amount of tau and progranulin in the brain therefore linking all this genes into a common pathway. As little is known about the functions of UBAP1 or progranulin in the brain we propose study the effects of progranulin on cells and characterise the distribution and function of UBAP1 and explore how it controls the levels of tau and progranulin. This work will help us to gain understanding to the biological problems causing FTLD. This knowledge will help in diagnosis and in the development of systems to produce a treatment, ultimately helping people with FTLD.

Technical Summary

Neurodegenerative diseases of our progressively more aged society are becoming an increasing social and economic burden. Frontotemporal lobar degeneration (FTLD) is the second most common form of dementia after Alzheimer‘s disease. Up to 40% of patients have a family history of this disease indicating a large genetic component to its aetiology. Approximately 5% of cases are caused by mutations in the MAPT gene encoding the microtubule associated protein, tau. Patients with MAPT mutations display a prominent tau-based neuropathology at autopsy. Around a further 5% of cases are caused by null-mutations of the pleiotropic growth factor, progranulin (PGRN) and the neuropathological features of these comprise of neuronal inclusions containing ubiquitinated TDP-43 protein. Until the discovery of mutations in PGRN very little was known about the function of this protein in the CNS. Preliminary data: Using linkage disequilibrium mapping of the recently reported FTLD ch9p linkage region, we identified genetic association of UBAP1 (Ubiquitin Associated Protein 1) within our FTLD cohort (214 patients, 286 controls; MAPT and PGRN mutation -ve). Analysis revealed SNPs/haplotypes were consistently associated with a maximum OR of 1.71 (95% CI 1.20-2.44, P=0.003). Crucially, we successfully replicated this association in a Dutch FTLD cohort (230 FTLD cases, 484 controls) with a maximum haplotype association of OR 1.39 (95% CI 1.02-1.89, P= 0.033). This argues that UBAP1 is a novel risk factor for FTLD and likely the gene responsible for linkage to this region. Using antibodies to UBAP1 we have shown this protein co-localises with tau in the neuronal perikaryon in FTLD. Furthermore, UBAP1 interacts with progranulin demonstrated by immunoprecipitation. These data suggest UBAP1 maybe important in regulating the amounts of these proteins via the ubiquitin proteosome system. I propose to identify and functionally characterise the genetic variants driving the UBAP1 association and charterise UBAP1 in human brain and existing mouse models of FTLD. In addition, we have shown that PGRN treatment of primary neurons and glia activates ERK. I propose to investigate the downstream effects of this signalling pathway using microarray analysis and to identify PGRN‘s receptor using affinity chromatography. Finally, I will investigate the role of UBAP1 in regulating levels of tau and PGRN using siRNA knockdown and expression of known UBAP1 mutations. This work could provide a paradigm shift in our understanding of the aberrant biological pathways controlling proteins important in FTLD and other neurodegenerative diseases. This work could highlight potential therapeutic targets.

Publications

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Bennion Callister J (2014) Pathogenesis/genetics of frontotemporal dementia and how it relates to ALS. in Experimental neurology

 
Description Project grant
Amount £110,000 (GBP)
Funding ID ARUK-PG2012-18 
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2012 
End 08/2013
 
Description Wellcome Trust/MRC Consortia Grant for Neurodegenerative disease
Amount £4,500,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2010 
End 02/2015
 
Title UBAP1 monoclonal antibody 
Description we have developed a monoclonal antibody to UBAP1 that is good for neuropathological diagnosis 
Type Of Material Antibody 
Year Produced 2008 
Provided To Others? Yes  
Impact none 
 
Description FTD+ALS chromosome 9 gene hunt 
Organisation National Institute on Aging
Country United States 
Sector Public 
PI Contribution we are helping in the identification of the chr9p FTD+ALS gene
Collaborator Contribution They have provided exome sequencing and whole genome genotyping for us
Impact none yet. multi-disciplinary involving geneticists, biochemists, pathologists and neurologists
Start Year 2009
 
Description FUS and FTLD 
Organisation King's College London
Department Institute of Psychiatry, Psychology & Neuroscience
Country United Kingdom 
Sector Academic/University 
PI Contribution we have contributed in writing a grant to work together on FUS, TDP-43 and progranulin in frontotemporal dementia and motor neuron disease
Impact £4.8M Wellcome Trust/MRC neurodegenerative disease collaborative grant
Start Year 2008
 
Title Identification of the chr9 FTD+MND gene 
Description patent to protect the genetic test for the hexanucleotide expansion causing FTD and MND 
IP Reference WO2013030588 
Protection Patent application published
Year Protection Granted 2012
Licensed No
Impact we can now test for the most common genetic cause of MND - mutation is found in 1 out of every 12 patients
 
Description Interview for BBC radio Manchester 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Media (as a channel to the public)
Results and Impact Interview on the breakfast show about a grant I was awarded

raised awareness of FTD
Year(s) Of Engagement Activity 2012
 
Description Talk to the public 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact As part of World Alzheimer's Day the Alzheimer's Research Trust organised a set of talks to the public about dementia research in Manchester

It was cover by local press raising the awareness to the public of the research we do in Manchester
Year(s) Of Engagement Activity 2009
 
Description lay talk to public 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact I gave a talk to the public about dementia and my research

The Alzheimer's Research Trust who helped organise the event got goos feedback from those who attended
Year(s) Of Engagement Activity 2009