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2017 Grants - Sharoar
Roles of DCTN6 in Tubular ER Clustering and DNs Formation in Alzheimer’s Disease
Md. Golam Sharoar, Ph.D.
Cleveland Clinic Foundation
2017 Alzheimer’s Association Research Fellowship (AARF)
Do low levels of the protein DCTN6 contribute to brain changes associated with Alzheimer’s disease?
In Alzheimer’s disease, the protein fragment beta-amyloid accumulates into plaques around nerve cells that can impair their function. Nerve cells use long branch-like extensions to communicate, but when surrounded by beta-amyloid the extensions become damaged and are called dystrophic neurites (DNs). Studies in mice have shown that DNs are associated with learning and memory problems.
Md. Golam Sharoar, Ph.D., and colleagues have found that abnormal accumulation of cellular structures called tubular endoplasmic reticulum (ER) can contribute to the formation of DNs in the Alzheimer’s brain. Normally tubular ER help to transport proteins to different parts of the cell, but in Alzheimer’s disease something triggers tubular ER to abnormally cluster in DNs.
Dr. Sharoar hypothesizes that low levels of a protein called DCTN6 (Dynactin Subunit 6) may lead to the formation of DNs in Alzheimer’s. DCTN6 is a protein that helps maintain the normal transport of tubular ER to different places in the nerve cell. The researchers will use nerve cells growing in laboratory dishes to study how DCTN6 affects the movement and accumulation of tubular ER. In other studies, the researchers will increase brain levels of DCTN6 in mice as they age and determine if this can reduce abnormal clustering of tubular ER. They will specifically focus on nerve cells in the hippocampus, a brain region important for memory and known to be affected early in Alzheimer’s disease.
These studies could shed new light on the molecular mechanisms that underlie nerve cell damage in Alzheimer’s disease. A better understanding of these mechanisms can help scientists to design drugs that target these pathways to help slow, halt or prevent Alzheimer’s disease.