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Yongjie Zhang, Ph.D.
Mayo Clinic Jacksonville
Jacksonville, FL - United States
Various brain diseases have different effects on the body and behavior. Frontotemporal dementia (FTD), for example, is a type of early-onset dementia with changes in personality and emotions; while amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, affects nerves controlling movement. Yet both disorders may share similar underlying biological mechanisms. In recent studies, scientists have found that both FTD and ALS may involve a mutated form of the gene called chromosome 9 open reading frame 72 (C9ORF72). This genetic mutation appears to promote the generation of harmfully-shaped proteins called dipeptide-repeat proteins (DPRs). DPRs can clump together abnormally to form protein aggregates that may promote brain cell damage and death in both FTD and ALS.
In recent experiments Yongjie Zhang, Ph.D., and colleagues generated synthetic DPR proteins. They found that one of these DPR proteins, called GFP-(GA) 50, was more likely than the others to clump abnormally. Moreover, using nerve cells grown in laboratory dishes, this protein interacted with another protein called valosin-containing protein (VCP) to induce a stress response in cells’ endoplasmic reticulum, a specialized compartment of the cell where proteins are produced. Stress in this compartment can lead to cellular damage and death.
For their current study, Dr. Zhang and colleagues will further explore these findings with additional studies using nerve cells in laboratory dishes and confirming in animal models. Their results could shed new light on the mechanisms underlying cellular degeneration in both FTD and ALS. Abnormal protein clumping is a common hallmark of many brain diseases, suggesting these results may also be applicable to Alzheimer’s disease and Parkinson’s disease. These studies could help identify biological mechanisms that underlie the accumulation and clumping of proteins and help lead to the development of new treatments for brain diseases.
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