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.
The Nixon Lab (work by Dr. David Yuan) has redefined the structure and function of neurofilaments, a major constituent of the neuronal cytoskeleton, reversing dogmas taught in science textbooks, including the subunit structure, mode of transport, and roles in neuronal function. The discovery that neurofilament subunits regulate neurotransmitter receptors, including Dopamine D1, has revealed new insights into mechanisms of addiction and opened a new field of research.