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2017 Grants - St. George-Hyslop
Role of Intrinsically Disordered Proteins in Fronto-Temporal Dementia
Peter H. St. George-Hyslop, M.D.,
FRCPC Governing Council of the University of Toronto
2017 Zenith Fellows Award (ZEN)
How does a unique protein called FUS become abnormally modified to promote the development of frontotemporal dementia?
Frontotemporal dementias (FTDs) are a group of brain diseases characterized by the early onset of dementia (occurring by one's 40s or 50s) along with changes in personality and emotions. These diseases get their name from the fact that they affect frontotemporal nerve cells, which exist in the front and side (temporal) regions of the brain. FUS (an abbreviation for 'fused in sarcoma') is a protein implicated in some types of FTD. The FUS protein forms clumps in FTD brains, similar to the way beta-amyloid protein forms amyloid plaques in the brains of people with Alzheimer's disease. Though evidence suggests that FUS clumps may promote nerve cell damage in FTD, scientists do not yet understand exactly how they exert their damage.
In preliminary research, Peter H. St. George-Hyslop, M.D., FRCPC, and colleagues have studied the role of FUS in another brain disorder called amyotrophic lateral sclerosis (also known as ALS or Lou Gehrig's disease). They found that people with ALS have variations of FUS that develop clumps of usual consistency, different from clumps of amyloid found in Alzheimer's or Parkinson's disease. These misshapen clumps of protein accumulate and impair motor neurons of the spinal cord, which causes the debilitating effects on muscle control as seen in ALS. The researchers also noted that similar clumps of FUS molecules appear in the brain cells of people with FTD. However, these molecules are normal proteins, not variations. They appear to develop clumps because of changes in the way they are chemically processed within the brain cells.
For their current grant, Dr. St. George-Hyslop and colleagues will use cultured brain cells to determine exactly how FUS protein molecules clump and become toxic in FTD. Specifically, they will identify the proteins that cut and/or chemically modify FUS in frontotemporal neurons. They will then assess how changes in these processing molecules might promote FUS clumping — and how the clumping, in turn, may damage the brain cells.
The results of this effort could refine our understanding of how FUS protein works in the brain, and how alterations of FUS may lead to declines in brain function. Ultimately, such knowledge could lead to a FUS-targeted therapy for FTDs.