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2008 Grants - Gong
Fbx2-Mediated Ubiquitin Pathway; A Novel Route for BACE1 Degradation
Bing Gong, M.D.
Columbia University Medical Center
New York, New York
2008 Investigator-Initiated Research Grant
The protein fragment beta-amyloid is a key suspect in Alzheimer's disease. People with Alzheimer's tend to develop beta-amyloid accumulations called plaques. This protein fragment is clipped in a two-stage process from its parent molecule, amyloid precursor protein (APP). The first cut is made by a protein called the beta APP cleaving enzyme 1 (BACE1).
Research has found that the protein ubiquitin may regulate BACE1 levels in the brain. Ubiquitin appears to attach itself to unwanted proteins, tagging them for degradation. This process is called ubiquitinization. Researchers believe that by inhibiting ubiquitinization, brain levels of BACE1 will increase and spur the production of beta-amyloid. However, the exact biological mechanisms underlying ubiquitinization of BACE1 are unknown.
In preliminary studies with mice, Bing Gong, M.D., and colleagues analyzed the effects of ubiquitin-C-terminal hydrolase (Uch-L1), a key enzyme in the ubiquitinization process. Their research suggested that by increasing the activities of Uch-L1, one could increase the ubiquitinization of BACE1.
For this proposed grant, Dr. Gong and colleagues will determine whether Uch-L1 is involved in BACE1 degradation. They will study the enzyme's effects in both cultured neurons and in mice genetically engineered to develop Alzheimer-like symptoms.
Results of Dr. Gong's study could shed new light on the mechanisms underlying beta-amyloid accumulation in Alzheimer's disease. Such findings could lead to novel therapies for the disease.