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2015 Grants - Sharma
Tau Proteostasis by Cysteine String Protein-alpha (CSP-alpha)
Manu Sharma, Ph.D.
Weill Medical College of Cornell University
New York, New York
2015 New Investigator Research Grant
Can certain molecules help prevent the abnormal folding of tau protein and reduce abnormal tau accumulation in the Alzheimer’s brain?
In order for proteins to carry out their normal, specialized functions, they must assume a specific three-dimensional shape. But sometimes proteins do not "fold" properly when they are being made, and become "misfolded” -- assuming an abnormal shape and changing their function. Ordinarily, molecular mechanisms exist to break down or “correct” misfolded proteins before they can accumulate. However, researchers have found that these processes may be disrupted in many disorders that cause degeneration of the brain, including Alzheimer’s disease.
One key protein that becomes misfolded in Alzheimer’s is called tau. Normally tau helps maintain the structure and nutrient transport in nerve cells. Misfolded tau loses its ability to carry out this vital function and accumulates into structures called neurofibrillary tangles which are thought to be toxic to nerve cells. Researchers hypothesize that the mechanisms for ensuring proper tau folding have gone awry in Alzheimer's disease but it remains unclear how this happens.
Manu Sharma, Ph.D., and colleagues have identified several molecular mechanisms that may be linked to abnormal tau folding and accumulation. All of the mechanisms involve “chaperone proteins” which bind to other proteins and help them assume their correct shape. For example, the chaperone protein called cysteine string protein-alpha (CSP-α) stabilizes the properly folded tau protein, which may help prevent it from forming tangles. For their current studies, the researchers will use nerve cells grown in laboratory dishes and Alzheimer’s-like mice to determine how chaperone-linked mechanisms affect tau accumulation and nerve cell health.
The results of Dr. Sharma’s effort could improve our understanding of what triggers abnormal tau protein accumulation in the brain how this plays a role in Alzheimer’s disease and other dementias. These findings could also lead to the development of chaperone-related molecular therapies for different dementias, including Alzheimer’s disease.