The Genetics and Pathophysiology of Spinocerebellar Degeneration
Lead Research Organisation:
University College London
Department Name: Institute of Neurology
Abstract
With an ageing population, spinocerebellar ataxia (SCA) is an increasingly important problem with insidious progression and no specific treatment. The estimated prevalence in adults of non-acquired ataxia in the UK is 10,000 people (data from ataxia UK). This neurodegenerative disorder is selective and progressive causing neuronal loss in the cerebellum which defines the clinical and pathological picture. Genetic factors are known to render cerebellar neurons vulnerable to cell death but a large number of these factors are yet to be identified. In particular the common risk factors and disease modifiers of ataxia are poorly understood.
Using established genomic methods, cerebellar expression techniques, cell culture models and neuropathological investigations we will identify the disease processes and pathways that lead to spinocerebellar degeneration. Understanding these biological processes will help form a network of pathways to investigate environmental causes of ataxia, allow the development of treatments to inhibit or reverse the disease process and precisely characterise patients for clinical trials.
Using established genomic methods, cerebellar expression techniques, cell culture models and neuropathological investigations we will identify the disease processes and pathways that lead to spinocerebellar degeneration. Understanding these biological processes will help form a network of pathways to investigate environmental causes of ataxia, allow the development of treatments to inhibit or reverse the disease process and precisely characterise patients for clinical trials.
Technical Summary
Aims
The purpose of this research is to build a genetic framework and establish the functional pathways that lead to spinocerebellar degeneration.
My initial work will identify both the common as well as the rare genetic risk factors and disease modifiers of spinocerebellar ataxia. The effects on expression of these variants will be examined in normal cerebellar, affected lymphoblastoid and brain mRNA. Pathogenic and modifying variants and their interacting proteins will be further investigated with tissue culture and neuropathological approaches.
My current MRC fellowship has been very successful, achieving 4/5 goals with 15 months to go. This has allowed me to develop techniques and establish important collaborations, such as the ataxia DNA and brain bank collection, thus laying the groundwork for future projects.
Design and methodology
This project incorporates a number of strategies.
1. Investigation of genetic variation in pure spinocerebellar ataxia (SCA) of unknown aetiology and the identification of genetic modifiers of the polyglutamine associated SCAs:
(a) Genome wide association study (GWAS) in pure spinocerebellar ataxia. In a total of 1680 samples, structural changes, copy-number variation and disease associated SNPs will be identified. This will be replicated in a European/USA cohort.
(b) GWAS to identify age-of-onset (AOO) modifiers of SCA1, 2, 3, 6 and 7 in 1255 SCA cases from the UK and EUROSCA. This data will be replicated in Huntington‘s disease through the funded Euro-HD-study and we have further access to Japanese/USA/Chinese and Australian SCA cohorts.
(c) Deep sequencing for variants in the loci from 1(a) and (b) and for rare coding changes in candidate genes which include known ataxia genes, channel/inositol pathway genes, fly and yeast modifier screen genes.
2. Expression profiling: Many of the variants identified will be non coding and likely to act by altering gene expression. Analysing genome-wide cerebellar mRNA expression data will allow the identification of expression differences.
3. Functional investigation: Gene function and protein interactors will be investigated in affected lymphoblastoid/brain mRNA, transient or stable cell models and if a channel-gene is implicated we will collaborate with Hanna/ Schorge to perform channel electrophysiology.
4. Neuropathology: This resource has already proven vital to our research in the characterisation of neuropathological features and the investigation of interacting proteins.
Opportunities
A significant proportion of the genetic risk factors will be identified providing a framework of pathways to interrogate functionally. Defining these pathways will facilitate the identification of therapies and allow more effective trials by precise stratification of patient cohorts.
The purpose of this research is to build a genetic framework and establish the functional pathways that lead to spinocerebellar degeneration.
My initial work will identify both the common as well as the rare genetic risk factors and disease modifiers of spinocerebellar ataxia. The effects on expression of these variants will be examined in normal cerebellar, affected lymphoblastoid and brain mRNA. Pathogenic and modifying variants and their interacting proteins will be further investigated with tissue culture and neuropathological approaches.
My current MRC fellowship has been very successful, achieving 4/5 goals with 15 months to go. This has allowed me to develop techniques and establish important collaborations, such as the ataxia DNA and brain bank collection, thus laying the groundwork for future projects.
Design and methodology
This project incorporates a number of strategies.
1. Investigation of genetic variation in pure spinocerebellar ataxia (SCA) of unknown aetiology and the identification of genetic modifiers of the polyglutamine associated SCAs:
(a) Genome wide association study (GWAS) in pure spinocerebellar ataxia. In a total of 1680 samples, structural changes, copy-number variation and disease associated SNPs will be identified. This will be replicated in a European/USA cohort.
(b) GWAS to identify age-of-onset (AOO) modifiers of SCA1, 2, 3, 6 and 7 in 1255 SCA cases from the UK and EUROSCA. This data will be replicated in Huntington‘s disease through the funded Euro-HD-study and we have further access to Japanese/USA/Chinese and Australian SCA cohorts.
(c) Deep sequencing for variants in the loci from 1(a) and (b) and for rare coding changes in candidate genes which include known ataxia genes, channel/inositol pathway genes, fly and yeast modifier screen genes.
2. Expression profiling: Many of the variants identified will be non coding and likely to act by altering gene expression. Analysing genome-wide cerebellar mRNA expression data will allow the identification of expression differences.
3. Functional investigation: Gene function and protein interactors will be investigated in affected lymphoblastoid/brain mRNA, transient or stable cell models and if a channel-gene is implicated we will collaborate with Hanna/ Schorge to perform channel electrophysiology.
4. Neuropathology: This resource has already proven vital to our research in the characterisation of neuropathological features and the investigation of interacting proteins.
Opportunities
A significant proportion of the genetic risk factors will be identified providing a framework of pathways to interrogate functionally. Defining these pathways will facilitate the identification of therapies and allow more effective trials by precise stratification of patient cohorts.