Novel PSP risk loci revealed by genomewide association study
19th June 2011
A large international consortium, including members of the Reta Lila Weston Institute (RLWI) have just completed a genomewide association study to identify genetic loci other than the tau gene that are associated with progressive supranuclear palsy (PSP). The findings of this study were published in Nature Genetics in June 2011. PSP is a parkinsonian movement disorder that is distinct from Parkinson’s disease (PD) in that PSP brains are typified by tau protein pathology i.e. widespread microscopic inclusions within the neurons and glia consisting of abnormally aggregated tau protein. Furthermore, common variation that forms the H1 haplotype of the gene coding for tau, MAPT, on chromosome 17 is strongly associated with increased risk of PSP. In the past decade, we have focused on the functional basis of this association and our data suggest that this is due to increased production of the tau protein.
However, PSP is a sporadic disorder and the tau H1 haplotype does not necessarily cause PSP. It is clear that one or more other genetic risk loci combined with environmental triggers acting alone or in concert cause PSP. With advances in microarray-based technology, it is now possible to get a snapshot of the all 20,000-25,000 genes and non-coding regions between the genes in the human genome and compare common variation between affected individuals and normal unaffected controls. Using this technology, one can now identify any variants that are over- or under-represented in the disease group and thereby pinpoint the affected genes. However, due to the very small effect size of these associations, it is necessary to screen the variants in as large a number of disease and control individuals in order to obtain statistically meaningful results. Since PSP is a relatively rare disorder, this project required the formation of a large international consortium of clinical and scientific centres from Europe and the US so as to maximize the number of PSP cases in the study to a final cumulative total of nearly 2,100 cases with a large contribution of autopsy confirmed samples from the RLWI/Queen Square Brain Bank.
The genomewide study reiterated the role of the tau gene in PSP with the H1 haplotype a stronger contributor to disease risk than the ε4 allele of apolipoprotein E in Alzheimer’s disease. In addition, several other gene associations provide us with intriguing new insights into pathways involved in PSP pathogenesis, including brain myelination (MOBP gene), endoplasmic reticulum unfolded protein response (EIF2AK3 gene), trans-Golgi-endosomal vesicle fusion (STX6 gene). Several other genes showed strong associations, including IRF4, IL2/IL21 (intergenic) and CD8B that suggest the role of immune response in PSP.
These findings provide us with new avenues for the study of the causes of PSP and if the processes interact, leading to a common pathway involving tau.
The consortium was headed by Professor Gerry Schellenberg, University of Pennsylvania and included members of RLWI (Dr Rohan de Silva, Professors John Hardy and Andrew Lees). The project was funded by the CurePSP Foundation and the Peebler PSP Research Foundation.
Prof Lees First Lord Brain Memorial Lecture
20 May 2010
RLWI Director, Professor Andrew Lees was awarded the First Lord Brain Memorial Lecture "Brainwashed by the Black Stuff" that he delivered at the Royal London Hospital on June 24th at 5pm. Professor Lees is an alumnus of the Royal London and the lecture was introduced by Professor John Hardy.
Walter Russell Brain, 1st Baron Brain (October 23,
– December 29, 1966) was a British neurologist. He was principal author
of the standard work of neurology, Brain's Diseases of the Nervous
System, and longtime editor of the neurological medical journal,
Brain. In 1922 he was elected to the staff at Maida Vale Hospital
(merged in 1948 with the National Hospital for Neurology and
Neurosurgery). This was the start of an association with the National
Hospital which lasted all of his professional life.
21 May 2010
Complete sequences of monozygotic twins
affected by multiple sclerosis and the other unaffected
A recent letter in Nature from groups at UCSF and NCGR in New Mexico have reported the complete genomic sequencing of monozygotic (mz) twins with one of the twins affected by the devastating autoimmune demyelinating disorder, multiple sclerosis (MS). They compared the complete genome sequence of one discordant MS mz twins and the transcriptome and epigenome sequences of CD4+ lymphocytes of three other discordant mz twins. Interestingly, the study failed to identify any differences between genome sequences, gene expression or the epigenome.
Mutant Parkinson's Zebrafish
19 May 2010
Zebrafish with deleted WD40 region of the LRRK2 gene developed at the Genome Institute of Singapore resulted in L-DOPA responsive movement deficits and neuronal loss and these a rescued by the normal protein.
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