New genes for risk and progression of rare brain disease identified

There are new genetic clues on risk factors and biological causes of a rare neurodegenerative disease called progressive supranuclear palsy (PSP), according to a new study from an international genetics team led by researchers from the Perelman School of Medicine at the University of Pennsylvania. In the largest genetics study of the disease, three new genes associated with risk for PSP were identified and two additional genetic variants affecting risk for PSP were confirmed. The paper appears in online in Nature Genetics. This gives new insight into a disease that has intriguing contrasts and similarities to other neurodegenerative diseases, including Parkinson's disease, frontotemporal dementia (FTD) and Alzheimer's disease.
"PSP is a devastating disease with no available treatments. This work increases what we know not only about the genetics but also about the underlying cause of the disease," said Gerard Schellenberg, PhD, professor of Pathology and Laboratory Medicine in the Perelman School of Medicine at the University of Pennsylvania and the study's senior author. "We hope this work not only will benefit patients with PSP, but will also increase our understanding of related more common diseases, such as Alzheimer's disease."
Progressive supranuclear palsy (PSP), a form of frontotemporal dementia, affects around 3-6 people per 100,000 and, after Parkinson's disease, is the second most common cause of degenerative parkinsonism. The disease is characterized by a difficulty coordinating eye movement, imbalance and gait instability, stiff movements, mood and emotional changes. Biologically, PSP is primarily caused by an abnormal accumulation of tau protein, which is well-known for its secondary role in Alzheimer's disease. Both environmental insults (i.e. repetitive brain trauma) and inherited factors contribute to the risk of developing tauopathies.
In a genome wide association (GWA) study comparing 1,114 autopsy-confirmed cases of PSP to 3,287 control subjects, researchers found significant genetic variations in three regions, at EIF2AK3, STX6 and MOBP. The study was replicated with a second set of subjects (1,051 clinically diagnosed with PSP, compared to 3,560 unique controls).

Three newly-identified genes include:
EIF2AK3 is a gene that encodes for endoplasmic reticulum unfolded protein response (UPR) which clears potentially toxic misfolded proteins. UPR disruption can influence PSP risk, according to researchers, and modifying the UPR has the potential to modify risk and possibly the course of disease.
STX6 encodes a protein called syntaxin 6 (Stx6) that typically shuttles vesicles within the cell, but genetic variation at STX6 may change intracellular transport or cause toxin absorption, contributing to PSP disease development.
The function of MOBP and the protein it encodes, MOBP, is still unclear, but the protein is found in brain regions affected in PSP and may be involved in myelin formation.

**Source: University of Pennsylvania School of Medicine