UK Parkinson's Disease Consortium - UKPDC
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A study published in Brain, led by researchers
at UCL Institute of Neurology, has shown that genetic mutations which
cause a decrease in dopamine
production in the brain and lead to a form of childhood-onset Dystonia,
also play a role in the development of Parkinson’s disease.
The new Leonard Wolfson Experimental Neurology Centre (LWENC) has opened for clinical studies and trials
In this paper Claudia Manzoni studies how fibroblast
cells from people with Parkinson’s disease caused by mutations in LRRK2
react to starvation. Although the changes are quite subtle, there are
differences between the way that fibroblasts that contain mutant LRRK2
respond to being starved – suggesting that there may be changes in the
way that these cells regulate a key process called autophagy (a term
which comes from the greek meaning to eat yourself, and is one of the
ways that cells get rid of waste and recycle proteins and organellles).
Research led by consortium researchers Dr Helene Plun-Favreau (UCL Institute of Neurology) and Dr Alex Whitworth (University of Sheffield), and collaborator Dr Heike Laman (University of Cambridge), has discovered how genetic mutations linked to Parkinson’s disease might play a key role in the death of brain cells, potentially paving the way for the development of more effective drug treatments. In the new study, published in Nature Neuroscience, the team of cross-institutional researchers showed how defects in the Parkinson’s gene Fbxo7 cause problems with mitophagy. More...
Mutations in LRRK2 are the most common genetic cause of Parkinson’s disease. Here, Claudia Manzoni talks about her research (funded by the Rosetrees Trust and the Michael J. Fox Foundation) into what LRRK2 might be doing within the cell: Parkinson’s disease is a brain illness that afflicts 1 in 500 people in the UK. High profile patients, such as the actor Michael J Fox, the boxer Muhammad Ali and the late Pope John Paul II, have raised public awareness of Parkinson’s and its devastating impact. More...
The aim of our group is to translate recently discovered genetic risk traits for complex neurological and psychiatric conditions into a deeper understanding of pathogenesis. Until recently, the complexity of common neurological and psychiatric human diseases has made a genetic understanding of these conditions appear near impossible. Thus, the aetiology of the vast majority of non-mendelian cases remained obscure. However, this has changed in the last five years with the advent of genome wide association studies (GWAs). Using single nucleotide polymorphism (SNP) chips to screen simultaneously for >500,000 genetic polymorphisms, typically in >1000 cases and >1000 controls, genetic risk factors for common neurological and psychiatric diseases have been identified, including Parkinson’s disease, Alzheimer’s disease, bipolar disease and schizophrenia.
These studies have demonstrated what has long been suspected; that “normal” variability can contribute to the risk of developing common neurological and psychiatric diseases. Furthermore, the effects of genetic risk variants can be sufficiently substantial to be clinically relevant. Common variability in the a-synuclein gene (minor allele frequencies ~10%) can predispose to Parkinson’s disease with an odds ratio of ~1.5. Thus, the genetic risk factors being identified by GWAs are comparable to the effects of, for example, raised homocysteine levels in stroke (commonly caused by a polymorphism in MTHFR: minor allele frequency 35%, OR 1.65), a risk factor which is regularly measured and treated. Even when the effect sizes are much smaller the information generated by GWAs may provide a route to drug discovery. This is demonstrated by the recent identification of genes encoding the sites of actions of important drugs (e.g. statins) on the basis of genetic loci explaining <1% of the phenotypic variation in the population.
Thus, by providing insights into disease pathogenesis, GWAs of neurological and psychiatric diseases have the potential to help generate new therapeutic strategies. However, in order to meet this potential, statistical “hits” need to be translated into genes and pathways. While this may seem straight forward, excitement has been tempered by the realisation that knowing genetic risk variants has not provided an automatic understanding of pathogenesis in most cases. In general, whereas rare Mendelian causes of neurological disease usually follow readily apparent causal pathways (for example, by altering the amino acid sequence of the protein product), common low risk genetic variants identified by GWAs typically do not map to coding regions of the genome and some have not even mapped to recognisable genes. This makes it difficult to understand how they operate to predispose to disease and so precludes functional studies. Solving this problem is the inspiration for this group’s work.
The basis of our approach is the hypothesis that heritable differences in transcriptional regulation, which are present and measurable in control populations, are important drivers of pathology in the human central nervous system (CNS). If common heritable differences in transcriptional regulation can drive pathology in the CNS, then we would expect to find strong associations between the risk SNPs identified in GWAs for human CNS diseases and specific mRNA expression phenotypes of functional significance in control human brain.
The success of previous genotypic gene expression studies provides empirical evidence for the feasibility and potential of this approach. We aim to expand on this general approach by taking the novel steps of studying multiple brain regions from the same individuals and by taking account of splice variation. The former (regional expression) will result in a unique parallel data set, which will provide the opportunity to better describe the internal structure of mRNA expression in the human brain and so potentially identify a smaller number of key expression phenotypes for association testing making it easier to detect important trans effects. The latter (splice variation), recognises the evidence for the importance of alternative splicing specifically in brain and the functional diversity of splice variants of the same gene. Since splice variants can have opposing functions the biological interpretation of overall gene expression levels (as compared to exon-specific expression) is fraught with difficulty. Thus, we hope to provide rapid insights into complex neurological and psychiatric diseases and generate a unique resource for the neuroscience community.
Page last modified on 01 feb 11 13:39