Investigation of the Pathophysiology of Spinocerebellar Degeneration

Lead Research Organisation: University College London
Department Name: Unlisted

Abstract

Spinocerebellar degeneration is a neurodegenerative disorder identified as a single entity or as part of another condition. It can occur in an inherited or non-inherited form, which are often clinically identical. In spinocerebellar ataxia and other neurodegenerative disorders such as Alzheimer‘s disease a key feature is the laying down of pathological protein as deposits in the brain. Using cell models and analysis of brain tissue, the disease processes and pathways that lead to these diseases can be elucidated. This may in turn allow the development of techniques to inhibit or reverse the disease process.

This project aims to identify and characterise the genetic cause of a familial form of spinocerebellar ataxia. When the gene is found, it will be only the second gene to be found in families whose main problem is pure cerebellar ataxia. Given the clinical and pathological features of this type of ataxia it may represent an important previously unrecognised pathogenic mechanism. This gene will be characterised in many other ataxia families and in individuals with no family history. The function of the gene will be investigated in cell culture models and donated human brain tissue to identify how this gene causes disease.

Technical Summary

The aim of this research is to identify and characterise the processes that lead to spinocerebellar degeneration using clinical, genetic, neuropathological and cell biology approaches that are well established in the host and collaborating laboratories. Ataxia is a common neurological disorder presenting either as an isolated condition or part of another neurological disorder. In ataxia, like many other neurodegenerative disorders, disease protein is deposited in the brain and this process has been proposed to be responsible for the pathogenesis. However, there is increasing evidence that these protein aggregates may in fact protect neurons.

A combination of genetic fine mapping and candidate gene sequencing will be employed to identify the disease gene in a family with a type of spinocerebellar ataxia (SCA11) showing genetic linkage to the genomic region 15q14-15. There is no anticipation in this family and a large repeat expansion has been excluded. Haplotype analysis will also be carried out in other SCA families with a similar phenotype. When identified, the SCA11 gene will be characterised in terms of its structure and pathological tissue expression by Northern and Western blotting analyses with the human SCA11 cDNA and with raised antibodies recognising the SCA11 protein respectively. Subsequently, other SCA families and sporadic cases with this common phenotype will be screened for the SCA11 molecular defect. The functional effects of the SCA11 defect will be analysed in transient and stable neuronal cell lines expressing the SCA11 molecular defect. The expressed proteins will then be investigated using a variety of antibodies recognising molecular routes and pathways implicated in the pathological process of other SCA subtypes.

Together with the cell biology studies, immunohistochemistry using the developed SCA11 antibodies and other primary antibodies will be performed in affected SCA11 brains and compared with other neurodegenerative diseases. Functional studies of the disease protein associated with SCA11 will be carried out using a yeast genetic two-hybrid screen with the aim of identifying interacting proteins and molecular pathways involved in disease. Proteomic studies will then be used to further characterise protein complexes and investigate their role in SCA11 pathogenesis.

This approach will identify, characterise and determine the function of the SCA11 gene and its encoded protein. Like SCA6, SCA11 may prove to be part of a novel mechanism of spinocerebellar degeneration. Deciphering the disease processes and protein interactions in spinocerebellar degeneration and other neurodegenerative diseases should ultimately lead to the development of therapeutic strategies.

Publications

10 25 50

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Schneider SA (2012) SPG11 Presenting with Tremor. in Tremor and other hyperkinetic movements (New York, N.Y.)

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Schottlaender LV (2014) Multiple system atrophy and repeat expansions in C9orf72. in JAMA neurology

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Schottlaender LV (2014) Mutant COQ2 in multiple-system atrophy. in The New England journal of medicine

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Schreglmann SR (2016) VPS13C-Another Hint at Mitochondrial Dysfunction in Familial Parkinson's Disease. in Movement disorders : official journal of the Movement Disorder Society

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Setó-Salvia N (2012) Glucocerebrosidase mutations confer a greater risk of dementia during Parkinson's disease course. in Movement disorders : official journal of the Movement Disorder Society

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Silveira-Moriyama L (2013) Clinical features of childhood-onset paroxysmal kinesigenic dyskinesia with PRRT2 gene mutations. in Developmental medicine and child neurology

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Stamelou M (2014) The phenotypic spectrum of DYT24 due to ANO3 mutations. in Movement disorders : official journal of the Movement Disorder Society

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Stamelou M (2013) Dystonic opisthotonus: a "red flag" for neurodegeneration with brain iron accumulation syndromes? in Movement disorders : official journal of the Movement Disorder Society

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Tucci A (2014) Novel C12orf65 mutations in patients with axonal neuropathy and optic atrophy. in Journal of neurology, neurosurgery, and psychiatry

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Tucci A (2010) Genetic variability at the PARK16 locus. in European journal of human genetics : EJHG

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Wiethoff S (2017) Pure Cerebellar Ataxia with Homozygous Mutations in the PNPLA6 Gene. in Cerebellum (London, England)

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Xiromerisiou G (2012) THAP1 mutations and dystonia phenotypes: genotype phenotype correlations. in Movement disorders : official journal of the Movement Disorder Society

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Xiromerisiou G (2012) Identical twins with Leucine rich repeat kinase type 2 mutations discordant for Parkinson's disease. in Movement disorders : official journal of the Movement Disorder Society

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Xiromerisiou G (2013) THAP1 mutations in a Greek primary blepharospasm series. in Parkinsonism & related disorders

 
Description Improved and larger range of neurogenetic tests
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
Impact Improved and larger range of neurogenetic tests. This leads to greater research and a better service for patients
 
Description BMA project grant
Amount £21,000 (GBP)
Organisation British Medical Association (BMA) 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2007 
End 01/2010
 
Description CRBC project grant/CRBC
Amount £98,000 (GBP)
Organisation National Institute for Health Research 
Department UCLH/UCL Biomedical Research Centre
Sector Academic/University
Country United Kingdom
Start 06/2009 
End 05/2011
 
Description Equipment award Wellcome Trust
Amount £661,363 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2011 
End 07/2016
 
Description MRC Project Grant
Amount £522,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 01/2011 
End 01/2015
 
Description MRC Research Grant (The Pathophysiology of Spinocerebellar degeneration)
Amount £1,600,000 (GBP)
Funding ID G0802760 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 02/2010 
End 01/2015
 
Description PhD studentship to work on IBM and neuromuscular disorders from the Saudi Government
Amount £150,000 (GBP)
Organisation Government of Saudi Arabia 
Sector Public
Country Saudi Arabia
Start 09/2016 
End 09/2020
 
Description UCL CBRC equipment grant
Amount £339,000 (GBP)
Organisation National Institute for Health Research 
Department UCLH/UCL Biomedical Research Centre
Sector Academic/University
Country United Kingdom
Start 08/2011 
End 08/2016
 
Description Wellcome Trust Equipment Grant
Amount £661,363 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2011 
End 08/2016
 
Description Wellcome Trust Strategic Award
Amount £980,000 (GBP)
Funding ID The Wellcome Trust (equipment and the Synaptopathies strategic award (104033/z/14/z) 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2015 
End 04/2020
 
Title Genome sequencing and GeCIP 
Description Genome sequencing and GeCIP 
Type Of Material Technology assay or reagent 
Year Produced 2015 
Provided To Others? Yes  
Impact Genome sequencing and GeCIP 
URL http://www.genomicsengland.co.uk
 
Title Muscle international registry and biobank 
Description Muscle international registry and biobank 
Type Of Material Database/Collection of Data/Biological Samples 
Year Produced 2013 
Provided To Others? Yes  
Impact Muscle international registry and biobank 
 
Title Synaptopathies collaboration 
Description Synaptopathies collaboration 
Type Of Material Biological samples 
Year Produced 2015 
Provided To Others? Yes  
Impact Synaptopathies collaboration 
 
Title SOLVE-RD, Coriell, Neurobiobank database of samples, tissue 
Description SOLVE-RD, Coriell, Neurobiobank database of samples, tissue: all anonymous Important for genetics and analysis 
Type Of Material Database/Collection of data 
Provided To Others? No  
Impact SOLVE-RD, Coriell, Neurobiobank database of samples, tissue: all anonymous Important for genetics and analysis 
 
Title Synaptopathies collaboration 
Description Synaptopathies collaboration 
Type Of Material Database/Collection of data 
Year Produced 2015 
Provided To Others? Yes  
Impact Synaptopathies collaboration 
 
Description Ataxia UK 
Organisation Ataxia UK
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Information and genetic analysis of patients
Collaborator Contribution Made members aware of our work, identified patients and families
Impact Publications, made UK patients with Ataxia more aware
Start Year 2006
 
Description Athens collaboration on ataxia and neuropathy 
Organisation National and Kapodistrian University of Athens
Department Neurology Athens
Country Greece 
Sector Academic/University 
PI Contribution Large Greek study on ataxia and neuropathy in Greece
Impact Large Greek study on ataxia and neuropathy in Greece
Start Year 2010
 
Description BMA 
Organisation British Medical Association (BMA)
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Funding and publication
Collaborator Contribution Funding and good press for our research
Impact Funding and publication
Start Year 2007
 
Description Cambridge collaboration on Dog ataxia and neuropathy. 
Organisation University of Cambridge
Department Department of Veterinary Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Cambridge collaboration on Dog ataxia and neuropathy. We are working on the genetics of neuropathy and ataxia in dog models of human disease
Collaborator Contribution Dog tissue
Impact Ongoing work
Start Year 2010
 
Description Childhood Motor Neuron Disease consortium 
Organisation Great Ormond Street Hospital (GOSH)
Department Department of Neurology
Country United Kingdom 
Sector Hospitals 
PI Contribution Collaborative group that have collected clinical details, cells, DNA and treatment responses on Childhood Motor Neuron Disease
Collaborator Contribution Collaborators have provided clinical details, cells, DNA for exome sequencing and gene identification
Impact A number of DNA samples and fibroblasts collected
Start Year 2011
 
Description Childhood Motor Neuron Disease consortium 
Organisation University of Pennsylvania
Department Department of Neurology
Country United States 
Sector Academic/University 
PI Contribution Collaborative group that have collected clinical details, cells, DNA and treatment responses on Childhood Motor Neuron Disease
Collaborator Contribution Collaborators have provided clinical details, cells, DNA for exome sequencing and gene identification
Impact A number of DNA samples and fibroblasts collected
Start Year 2011
 
Description Childhood Motor Neuron Disease consortium 
Organisation University of Sydney
Department Brain and Mind Research Institute
Country Australia 
Sector Academic/University 
PI Contribution Collaborative group that have collected clinical details, cells, DNA and treatment responses on Childhood Motor Neuron Disease
Collaborator Contribution Collaborators have provided clinical details, cells, DNA for exome sequencing and gene identification
Impact A number of DNA samples and fibroblasts collected
Start Year 2011
 
Description EUROSCA 
Organisation European Commission
Department EC FP6 Collaborative Projects
Country European Union (EU) 
Sector Academic/University 
PI Contribution Identification, screening and functional characterization of ataxia genes
Collaborator Contribution EUROSCA is a collaboration between researchers and clinicians working on ataxia. These has brought cases and techniques that have benefited my research.
Impact Publications as already give. Patients and clinical details of cases with ataxia
Start Year 2006
 
Description European Brain Bank Network 
Organisation Medical Research Council (MRC)
Department MRC UK Brain Banks Network
Country United Kingdom 
Sector Academic/University 
PI Contribution Brain tissue for our research
Collaborator Contribution Brain tissue for research
Impact Brain tissue for our research
Start Year 2006
 
Description European and American Brain Bank Network 
Organisation Medical Research Council (MRC)
Department MRC UK Brain Banks Network
Country United Kingdom 
Sector Academic/University 
PI Contribution This collaboration has given valuable patient brain tissue to our research
Collaborator Contribution Collaborated with tissus
Impact Publications and the addition of important tissue resources
Start Year 2006
 
Description FARA collaboration to share data 
Organisation Friedreich's Ataxia Research Alliance
Country United States 
Sector Charity/Non Profit 
PI Contribution The Friedreich's ataxia samples collected from around the world in this award were imperative in gaining funding from FARA to genotype samples in the same way they have done on USA Friedreich's ataxia samples and the data shared
Collaborator Contribution Sharing of FRDA genotyping
Impact None as yet
Start Year 2020
 
Description Genomics England Genome Sequencing (100,000 genomes) and Neurology GeCIP (HH is co-lead) 
Organisation Genomics England
Country United Kingdom 
Sector Public 
PI Contribution Genomics England Genome Sequencing (100,000 genomes) and Neurology GeCIP (HH is co-lead)
Collaborator Contribution Genomics England Genome Sequencing (100,000 genomes) and Neurology GeCIP (HH is co-lead)
Impact Genomics England Genome Sequencing (100,000 genomes) and Neurology GeCIP (HH is co-lead)
Start Year 2015
 
Description Genomics England collaboration on new disease genes and risk factors 
Organisation Genomics England
Country United Kingdom 
Sector Public 
PI Contribution Collaboration on disease genomes
Collaborator Contribution Collaboration on disease genomes
Impact See publications in high impact journals such as Nature Genetics
Start Year 2019
 
Description Greek Collaboration on neurogenetics - Athens, Thessaloniki and Larisa 
Organisation National and Kapodistrian University of Athens
Department Neurology Athens
Country Greece 
Sector Academic/University 
PI Contribution Greek Collaboration on neurogenetics - Athens, Thessaloniki and Larisa Sharing of DNA and clinical details on series and families
Collaborator Contribution Greek Collaboration on neurogenetics - Athens, Thessaloniki and Larisa Sharing of DNA and clinical details on series and families
Impact Sharing of families and data
Start Year 2011
 
Description Laboratory of Neurogenetics, NIA 
Organisation National Institute on Aging
Country United States 
Sector Academic/University 
PI Contribution Collaborating on techniques such as developing DNA arrays and exome sequencing in our lab
Collaborator Contribution Collaboration on techniques and patients
Impact Joint publications and techniques
Start Year 2006
 
Description Laboratory of Neurogenetics, NIA and NIH, USA 
Organisation National Institute on Aging
Country United States 
Sector Academic/University 
PI Contribution Data, cases, publications
Collaborator Contribution Sharing of data, cases and techniquesData and publications
Impact Publications, assistance with grants
 
Description Laboratory of Neurogenetics, NIA and NIH, USA 
Organisation National Institute on Aging
Country United States 
Sector Academic/University 
PI Contribution Data, cases, publications
Collaborator Contribution Sharing of data, cases and techniquesData and publications
Impact Publications, assistance with grants
 
Description Larisa Greek parkinsonism study 
Organisation University of Thessaly
Department Neurology Thessaly
Country Greece 
Sector Academic/University 
PI Contribution Larisa Greek parkinsonism study. Over 1200 Greek parkinsonian patients and controls collected and DNA extracted
Impact Over 1200 Greek parkinsonian patients and controls collected and DNA extracted. Work ongoing, GWAS underway
Start Year 2010
 
Description MRC Centre for Neuromuscular Diseases 
Organisation University College London
Department MRC Centre for Neuromuscular Diseases
Country United Kingdom 
Sector Academic/University 
PI Contribution The MRC Centre for Neuromuscular Diseases is an MRC funded centre set up to investigate the causes and identify treatments for neuromuscular diseases.
Collaborator Contribution The MRC Centre for Neuromuscular Diseases is an MRC funded centre set up to investigate the causes and identify treatments for neuromuscular diseases. I am a member and collaborator in the The MRC Centre for Neuromuscular Diseases.
Impact The MRC Centre for Neuromuscular Diseases is an MRC funded centre set up to investigate the causes and identify treatments for neuromuscular diseases. I am a member and collaborator in the The MRC Centre for Neuromuscular Diseases.
Start Year 2006
 
Description MRC NMC 
Organisation University College London
Department MRC Centre for Neuromuscular Diseases
Country United Kingdom 
Sector Academic/University 
PI Contribution I am a member of the MRC Centre for Neuromuscular Diseases which has brought in very important collaborations between myself and Mike Hanna and Mary Reilly. We have generated considerable data, patient information and publications.
Collaborator Contribution I am a member of the MRC Centre for Neuromuscular Diseases which has brought in very important collaborations between myself and Mike Hanna and Mary Reilly. We have generated considerable data, patient information and publications.
Impact I am a member of the MRC Centre for Neuromuscular Diseases which has brought in very important collaborations between myself and Mike Hanna and Mary Reilly. We have generated considerable data, patient information and publications.
Start Year 2008
 
Description MSA Trust 
Organisation Sarah Matheson Trust for MSA
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Data, tours of the lab, newsletter information
Collaborator Contribution Patients, we write a research update in the newletter, many patients have given blood and donated their brain as a result of the research
Impact Publications, data, tours of the lab, newsletter information
Start Year 2006
 
Description NORD 
Organisation National Organization for Rare Disorders (NORD)
Country United States 
Sector Charity/Non Profit 
PI Contribution Patient's referred and a grant
Collaborator Contribution Patient's referred and a grant
Impact Patient's referred and a grant
Start Year 2008
 
Description Neuromics FP7 collaboration 
Organisation European Commission
Department Seventh Framework Programme (FP7)
Country European Union (EU) 
Sector Public 
PI Contribution Neuromics FP7 collaboration where we received funding for a post-doc (to prof hanna) and also funding for sequencing. There was significant collaboration and added value from this collaboration with shared results and materials
Collaborator Contribution Shared results and materials - genome/exome sequencing, functional data and patient materials
Impact Publications, collaboration and preparation for other rare disease grants
Start Year 2012
 
Description Neuromics neurogenetics collaboration 
Organisation Eberhard Karls University of Tubingen
Department Neuromics
Country Germany 
Sector Academic/University 
PI Contribution We are the channelopathy and ataxia part of the collaboration. Our role is exome sequencing, genetics and expression
Collaborator Contribution Groups working on several areas of genetics
Impact Recently started
Start Year 2012
 
Description PENN collaboration on Dog ataxia and neuropathy 
Organisation University of Pennsylvania
Department School of Veterinary Medicine (UPenn)
Country United States 
Sector Academic/University 
PI Contribution PENN collaboration on Dog ataxia and neuropathy. We are working on the genetics of neuropathy and ataxia in dog models of human disease
Collaborator Contribution Provided tissue and clinical details
Impact Joint grant submitted to NIH
Start Year 2010
 
Description Sakhalin Universitycollaboration 
Organisation Sakhalin State University
Country Russian Federation 
Sector Academic/University 
PI Contribution Collaboration on patients with Neuropathy in Russia
Impact ongoing
Start Year 2010
 
Description Sarah Matheson Trust for MSA 
Organisation Sarah Matheson Trust for MSA
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Brought patients and encouraged brain donation of MSA patients for our research
Collaborator Contribution Brought patients and encouraged brain donation of MSA patients for our research
Impact Publications, Brought patients and encouraged brain donation of MSA patients for our research
Start Year 2006
 
Description Synaptopathies consortium 
Organisation Partnership for Advanced Computing in Europe (PRACE)
Country Belgium 
Sector Academic/University 
PI Contribution Synaptopathies consortium: Wellcome Trust strategic award Sequencing in paroxysmal disorders with collaboration with Rothman, Kullmann, Hanna, Sisodiya, Goadsy and others
Collaborator Contribution Families and samples
Impact Built up a significant cohort
Start Year 2015
 
Description University of Tehran 
Organisation University of Tehran
Country Iran, Islamic Republic of 
Sector Academic/University 
PI Contribution Prof Elahe has provided many inportant families for our research and we currently share a PhD student
Collaborator Contribution Prof Elahe has provided many inportant families for our research and we currently share a PhD student
Impact Prof Elahe has provided many inportant families for our research and we currently share a PhD student
Start Year 2009
 
Description Wayne State University 
Organisation Wayne State University
Country United States 
Sector Academic/University 
PI Contribution Sharing of CMT1A patient data and DNA
Collaborator Contribution Sharing of CMT1A patient data and DNA
Impact Sharing of CMT1A patient data and DNA
Start Year 2008
 
Description dystonia genetics and functional gene collaboration 
Organisation Sanford Heart Hospital
Country United States 
Sector Hospitals 
PI Contribution Exome sequencing, fibroblast and expression studies
Collaborator Contribution dystonia genetics and functional gene collaboration
Impact DMRF joint grant
Start Year 2010
 
Description Ataxia Uk patient society 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact Information for people with ataxia

More patients keen to help with research
Year(s) Of Engagement Activity 2006,2007,2008,2009
 
Description Genomics England Genome Sequencing (100,000 genomes) and Neurology GeCIP (HH is co-lead) 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Genomics England Genome Sequencing (100,000 genomes) and Neurology GeCIP (HH is co-lead)
Year(s) Of Engagement Activity 2015
URL http://www.genomicsengland.co.uk
 
Description HSP society 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact HSP yearly meet and section in HSP booklet
Year(s) Of Engagement Activity 2012,2013