Scientists are one step closer to understanding the genes associated with the rare neurodegenerative disease, progressive supranuclear palsy (PSP), according to a study published in the current Nature Genetics. The genomewide association study was completed by an international consortium of researchers, including members of UCL Institute of Neurology’s Reta Lila Weston Institute (RLWI).

Progressive supranuclear palsy (PSP) is a parkinsonian movement disorder, affecting around 3-6 people per 100,000, and characterised by difficulty coordinating eye movement, imbalance and gait instability, still movements and emotional changes.

In the past two decades, scientists have been able to ascertain that patients with PSP show an abnormal accumulation of the tau protein in their brain (a protein also associated with Alzheimer’s disease) and that the risk of developing PSP is increased in patients with common variation in the gene that codes for tau, MAPT. So while data suggests that an increase in tau protein production is a factor in developing PSP, it is not clear whether this causes PSP. 

With advances in microarray-based technology that allow scientists to get a snapshot of the 20,000-25,000 genes and non-coding regions between the genes, this study compared the genetic variations between about 2,100 individuals with PSP to normal control subjects. The technology allows scientists to identify genetics 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 and because PSP is a relatively rare disorder, a large number of disease and control subjects was needed to obtain statistically meaningful results. A vast team of researchers from European and American clinical and scientific centres worked together to complete the study, including a large contribution of autopsy confirmed samples from the RLWI and Queen Square Brain Bank.

The results of the study reiterate the role of the MAPT gene in PSP and confirm that patients with the MAPT H1 haplotype variant have increased risk of PSP. It also identified several other gene regions associated with the risk of developing PSP: the MOPB gene (involved in myelin formation), the STX6 gene (which may change intracellular transport or cause toxic absorption) and the EIF2AK3 gene (which is involved in the clean up of potentially toxic misfolded proteins).

These findings provide researchers with new avenues for the study of the causes of PSP, and potentially lead to the investigation of new drug discovery targets.

The consortium was headed by Professor Jerry 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. Research at the RLWI and Queen Square Brain Bank are funded by The PSP Association and Brain Research Trust.

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