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Pharmacology & Physiology |
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Research Interest |
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Virgil Muresan, PhD |
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Contact Info: Office Phone: (973) 972-2392 |
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Vital cellular functions, including transmission of signals from one part of the cell to the other, rely on the transport of organelles and protein complexes to specific intracellular destinations. A large proportion of this transport occurs on cytoskeletal tracks, the microtubules, and is powered by specialized molecular motors, kinesins and cytoplasmic dynein. Our long-term goal is to understand how microtubule motors work, how they organize intracellular signaling pathways, and how their abnormal function may lead to disease. Presently, most of our research is disease-oriented. Starting from the analysis of axonal transport in neurodegenerative diseases (specifically, Alzheimer’s disease, Down’s syndrome, and lissencephaly), we became more and more interested in the mechanism of the disease, even if this transgressed the study of axonal transport. A case in point is the problem of phosphorylation of the amyloid precursor protein (APP), a culprit in Alzheimer’s disease. This posttranslational modification occurs normally in differentiated neurons, but is increased in Alzheimer’s disease, when it may alter APP metabolism and thus lead to plaque formation. We became interested in phosphorylation of APP, since it appeared to play a role in regulating its transport into axons. We have now dissected in detail the mechanism by which phosphorylation of APP leads to recruitment of the motor kinesin-1, initiating transport. At the same time, we have identified a novel signaling pathway (implicating the kinase JNK and the scaffolding protein JIP-3) that leads to this phosphorylation event. Moreover, this study also allowed us to gain insight into the function of phosphorylated APP in neurite extension. Finally, we were able to identify an alternative pathway for APP phosphorylation that implicates the kinase Cdk5 – not JNK, and prevails in degenerating neurons. A second case in point is the problem of neuritic plaque nucleation in Alzheimer’s disease, where we have proposed a novel mechanism for initiation of plaque formation. According to our hypothesis, plaque formation in cortical and hippocampal brain regions is seeded by amyloid-beta oligomers (derived through proteolysis from APP) that accumulate at the terminals of projections of brainstem neurons, which extend into the hippocampus and cortex. Thus, starting from the investigation of APP transport, our studies also shed light on the function of APP, on the abnormal APP metabolism during degeneration, and on the pathogenesis of Alzheimer's disease. |
