Characterization of ubiquitin inclusions in FTD-MND and MND

Lead Research Organisation: University of Cambridge
Department Name: Cambridge Centre for Brain Repair

Abstract

The Sheffield and Nottingham groups are directly involved with patient groups through the MNDA funded Care and Research Centres in those cities. The applicants will use the MNDA national and local meetings to present this work to carers and patients. Successful application of proteomic techniques to unlock the key molecular events in a human brain disease by using archival tissue will be of major interest in the general scientific media in terms of the current UK debate about the use of human tissues in research. The applicants will seek to bring any success in the project to general press attention.

Technical Summary

Neurodegeneration in the ageing CNS is characterised by protein dysmetabolism and the presence of protein aggregates. This process appears directly related to cell death and CNS dysfunction. Neurodegenerative diseases that were once defined solely on clinico-pathological grounds are increasingly assimilated into a classification based on the underlying protein dysmetabolism. These include tau (Alzheimer s disease, frontotemporal dementia/parkinsonism ch17 syndromes[FTDP-17], progressive supranuclear palsy, corticobasal degeneration etc.), alpha-synuclein (Parkinson s disease, Dementia with Lewy bodies, Multiple system atrophy etc), and a variety of other proteins associated with less common disorders (e.g. neurofilament, trinucleotide repeat expansion proteins etc.). They are all characterised by intracellular inclusions, predominantly composed by one of these proteins. The protein dysmetabolism almost invariably includes aggregation and fibrilisation which can be associated with ubiquitin-related protein metabolism, so that ubiquitin is variably co-localised to the inclusion bodies.
Amyotrophic lateral sclerosis (ALS) and related disorders remain outside this new molecular understanding because the underlying protein dysmetabolism has not been defined. This group of disorders are characterised by ubiquitylated inclusions (UBI) within neurons but the identity of the inclusion body protein(s) has not been elucidated by immunochemical, genetic or other strategies. Developments in several areas of science including understanding of the relationship between ALS and other disorders, microdissection technology, and diverse novel proteomic analytical approaches present a timely opportunity to investigate the identity of the UBI protein.
The significance of this problem could not be overstated for the field of ALS research. ALS genetics has, unlike for tau and a-synuclein, failed to deliver this data in either sporadic or familial disease. For the other common neurodegenerative diseases listed above knowledge of the pathogenesis of inclusion body formation has been the major impetus for research advances in the last decade. We propose a collaborative, interdisciplinary approach applied to human tissue samples and using proven, cutting-edge methods allied to expert clinical and pathological data to identify the protein present in UBI in ALS and frontotemporal dementia with ALS.

Publications

10 25 50

publication icon
Duyckaerts C (2015) PART is part of Alzheimer disease. in Acta neuropathologica

publication icon
Forrest SL (2019) Heritability in frontotemporal tauopathies. in Alzheimer's & dementia (Amsterdam, Netherlands)

publication icon
Goedert M (2006) Frontotemporal lobar degeneration through loss of progranulin function. in Brain : a journal of neurology

publication icon
Goedert M (2012) Frontotemporal dementia: implications for understanding Alzheimer disease. in Cold Spring Harbor perspectives in medicine

publication icon
Goedert M (2006) A century of Alzheimer's disease. in Science (New York, N.Y.)

 
Description FENS School on Neurodegenerative diseases
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
Impact The school was attended by students from different countries, some under-developed and the possibility was given to these students to be part of the international scientific community
 
Description Centre Grant
Amount £2,127,000 (GBP)
Organisation Multiple Sclerosis Society 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2011 
End 03/2016
 
Description Collaboration grant
Amount € 421,800 (EUR)
Funding ID Promotion of plasticity as a treatment for neurodegenerative conditions. 
Organisation European Commission 
Department Seventh Framework Programme (FP7)
Sector Public
Country European Union (EU)
Start 12/2008 
End 11/2012
 
Description PhD Studentship
Amount £65,000 (GBP)
Organisation University of Cambridge 
Department Cambridge Home & EU Scholarship Scheme (CHESS)
Sector Academic/University
Country United Kingdom
Start 10/2011 
End 09/2014
 
Description Project Grant
Amount £325,236 (GBP)
Funding ID ART-PG2011-20 
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2011 
End 09/2014
 
Description Project Grant
Amount £45,300 (GBP)
Organisation University of Cambridge 
Department Isaac Newton Trust
Sector Academic/University
Country United Kingdom
Start 07/2012 
End 06/2013
 
Description Project grant
Amount £247,900 (GBP)
Organisation Parkinson's UK 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2012 
End 01/2015
 
Description Project grant
Amount $75,000 (USD)
Organisation Cure PSP (Foundation for PSP/CBD and Related Brain Diseases) 
Sector Charity/Non Profit
Country United States
Start 06/2010 
End 04/2012
 
Description Project grant
Amount $48,000 (USD)
Organisation Dr. Scholl Foundation 
Sector Charity/Non Profit
Country United States
Start 12/2012 
End 07/2013
 
Description Senior Fellowship
Amount £288,816 (GBP)
Funding ID ART-SRF2010-1 
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2010 
End 12/2013
 
Description Target Validation
Amount $75,000 (USD)
Organisation Michael J Fox Foundation 
Sector Charity/Non Profit
Country United States
Start 08/2011 
End 09/2012
 
Title charcaterization of Brain pathology 
Description human brain and spinal cord tissue 
Type Of Material Model of mechanisms or symptoms - human 
Provided To Others? No  
Impact knowledge of the type of pathology present in frontotemporal dementia 
 
Description Clinical, genetic and pathological characterization of FTD cases 
Organisation University of Cambridge
Department Department of Clinical Neurosciences
Country United Kingdom 
Sector Academic/University 
PI Contribution investigated tau genetics and molecular pathological features
Collaborator Contribution providing brains from patients clinically well characterised
Impact the output is shown by papers published with Prof John Hodges
 
Description Protein characterization in ALS and FTD. 
Organisation University of Sheffield
Department Department of Neuroscience
Country United Kingdom 
Sector Academic/University 
PI Contribution We extracted proteins from tissue and run blots and mass spect
Collaborator Contribution Prof P. Ince and P. Shaw were co-applicant in the grant, they provided tissue from ALS and FTD patients and we discussed the results
Impact papers in the grant
 
Description Cambridge Science week 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact The talk was very well received and stimulate interest and discussion

Several people became interested in more depth on the topic according to the questions and interest
Year(s) Of Engagement Activity 2014
 
Description Conferences, patient groups, public seminars 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact Presented data at various types of meetings

Further collaborations
Year(s) Of Engagement Activity 2007,2008,2009
 
Description Lecture to summer school in Desenzano del Garda September 24-27, 2017 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact I gave a talk in the summer school about protein aggregation in neurodegenerative diseases and their meaning for disease progression
Year(s) Of Engagement Activity 2017
 
Description Pint of Science 2017 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact I gave a talk about the work we are carrying out in a pub to general public
Year(s) Of Engagement Activity 2017
 
Description Plenary Lecture to Neuroscience Undergraduate students of London University 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Schools
Results and Impact Plenary Lecture London Universities Neuroscience undergraduate students
Year(s) Of Engagement Activity 2016
 
Description Presentation to the Italian Cultural association "Il Circolo" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Invited to give a talk to a general audience on the state of art on Parkinson's and frontotemporal dementia to member of the public.

The attendee were excited by the result of our research and organised a small fund raising to support a 6 month visit from an Italian postdoctoral fellow.
Year(s) Of Engagement Activity 2012
 
Description Presentation to the Italian Society of Frontotemporal dementia lay members 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Supporters
Results and Impact Presentation of results on frontotemporal dementia study
Year(s) Of Engagement Activity 2015
 
Description Soapbox 
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 Public/other audiences
Results and Impact Given a talk about our work in Cambridge Market Square in occasion of the Soapbox event
Year(s) Of Engagement Activity 2016
 
Description Student organisation conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact I was invited to give a plenary lecture at the Meeting organised by London universities postgraduate student association
Year(s) Of Engagement Activity 2016