Regulation of APP Degradation and ABeta Secretion

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DESCRIPTION (provided by applicant): Our Laboratory has recently discovered a novel 240,000 MW protein that is intimately involved in the metabolism of amyloid precursor protein (APP) and AB production. The protein, called modifier of cell adhesion (MOCA), is expressed in CNS neurons but not glia, binds to presenilin and a number of other proteins, and is associated with neurofibrillary tangles in AD brain. The expression of MOCA in neurons leads to a dramatic increase in the rate of APP degradation and a lowering of AB production. It may therefore be an in vivo mechanism for maintaining a low level of Ab production by neurons and delaying the onset of AD. It is the goal of this proposal to understand how MOCA directs the destruction of APP and the subsequent loss of AB secretion. Toward this end, three hypotheses will be tested. The first is that MOCA alters either the kinetics or specificity of the classical ubiquitin-proteasome pathway. Ubiquitin independent degradation pathways are also considered. Second, because it has recently been shown that sumoylation alters the stability of APP, we will study the role of SUMO in MOCA dependent APP breakdown. Finally, MOCA null mice have been made to study the in vivo function of the MOCA protein. It is predicted that MOCA-deficient mice will have increased levels of AB and developmental abnormalities resulting from enhanced APP expression in neurons. These studies should clearly define the biological role of MOCA in the context of APP and lead to greater insight into how APP and Ab levels are regulated. If small molecules could be found which specifically mimic MOCA function, they could potentially be used to lower pathological AB levels in the brain. In addition, understanding how cells regulate the degradation of proteins is critical to the study of a wide range of diseases, particularly those in the nervous system that are characterized by the intracellular protein accumulation.