Head of LabRalph Nixon, MD, PhD
The research of the Nixon laboratory focuses on two aspects of neurobiology that govern the fate ofnormal and pathogenic proteins: the regulation of proteolytic processing and the control of protein export into axons and synapses. We have identified dysfunction of the endosomal-lysosomal system, involving altered endocytosis and mistrafficking of proteases to endosomes, as the earliest known pathologicalresponse of neurons in Alzheimer’s disease. Our cell modeling studies show early endosomes to be major generators of the toxic b-amyloid peptide and implicate dysfunction of endosomes in themechanism of b-amyloid accumulation in "sporadic" Alzheimer’s, the mostcommon form of the disease. Genetic manipulations of proteolytic systems in mice are being used, together with cell culture models, to determine the consequences of endosomal-lysosomal and calpain system dysfunction on processing of Alzheimer-related proteins, receptor-mediated signal transduction, and neuronal cell death pathways.
To maintain neural circuitry, neurons transport a large proportion of their newly synthesized proteins into axons. The perikaryal accumulation of specific cytoskeletal proteins - a pathological hallmark of Alzheimer’s, ALS, and other neurologic diseases - is believed to arise in part from impaired axonal transport. A second interest of our research is to identify the molecular determinants of cytoskeletal protein transport and assembly in neurons. For example, we are defining the minimum structural requirements for neurofilament translocation by studying axonal transport and axon ultrastructure in mice after targeted deletion or mutagenesis of each of the three neurofilament subunit genes. Neurofilament transport is also regulated by sequential protein phosphorylation, triggered in part by signals from oligodendroglial cells. We have been determining the signaling pathways, phosphorylation sites, and functional implications of these post-translational modifications. Disease relevance is also being explored in several behavioral and psychiatric settings.
Recent published and submitted work by Dr. David Yuan has redefined the structure and function of neurofilaments, a major constituent of the neuronal cytoskeleton, reversing several dogmas taught science textbooks, including the subunit structure, mode of transport, and roles in neuronal function. Specifically, the discovery that neurofilament subunits regulate neurotransmitter receptors, including the Dopamine D1 R, has revealed new insights into mechanisms of drug addiction and opened up a new field of research.
Nixon Lab Members
|Marty Berg - Research Scientist||Matteo Bordi - Postdoctoral Fellow||Dan Colacurcio - Postdoctoral Fellow
|Chunfeng Huo - Research Technician
|Pearl Lie - Postdoctoral Fellow||Ying Jiang - Research Scientist||Asok Kumar - Managing Director, EM Lab||Ju-Hyun Lee - Research Project Manager|
|Mary Kate McBrayer - Postdoctoral Fellow||Panaiyur Mohan - Senior Research Scientist||Anna Pensalfini - Postdoctoral Fellow||Corrinne Peterhoff - Research Technician|
|Pallabi Sarkar - Postdoctoral Fellow||Philip Stavrides - Research Technician||Dun-Sheng Yang - Research Scientist||Aidong (David) Yuan - Research Project Manager|