Beginning with a long-standing interest in molecular mechanisms underlying the normal development and maintenance of the nervous system, our work has recently expanded to include a major effort to understand molecular events causing neurodegenerative diseases such as Alzheimer's and FTDP-17 (Fronto-Temporal Dementia with Parkinsonism linked to chromosome 17). Our investigations focus upon the normal and pathological action of the microtubule associated protein, tau. Under normal circumstances, this tightly regulated protein controls microtubule dynamics, thereby regulating microtubule function. Proper microtubule function is, in turn, required for proper neuronal function and survival. On the other hand, tau dysfunction has long been linked to Alzheimer's disease pathology. Recent genetic analyses have demonstrated that mutations affecting either the primary structure of tau or the regulation of tau RNA alternative splicing cause neuronal cell death and dementia in FTDP-17; importantly, these mutations exhibit dominant rather than recessive phenotypes. In these disease conditions, tau is not microtubule associated but rather assembles into abnormal pathological fibers within necrotic neurons.

Our efforts to understand normal and pathological tau action employ a wide range of strategies and technologies, ranging from protein biochemistry to molecular biology to cell biology to biophysics. Among our major goals is to determine the precise mechanistic details by which tau regulates microtubule behavior, integrating high resolution in vitro biochemical and biophysical analyses with investigations in cells. In the past 1-2 years, these efforts have led to a new model for tau structure and function that fits in extremely well with the FTDP-17 genetics. In addition, in order to better understand the RNA splicing regulatory mutations that cause neurodegeneration, we are also attempting to determine the exact tau isoform expression levels in individual neurons derived from Alzheimer's, FTDP-17 and normal brains. Taken together, our many investigations are providing exciting mechanistic insights into how tau promotes the development and maintenance of the nervous system under normal circumstances as well as molecular mechanisms responsible for neurodegenerative diseases. The broad range of strategies that we have integrated into our laboratory effort have been possible because of our many collaborations with outstanding colleagues here at UCSB, including Drs. Kathy Foltz, Don Graves, MaryAnn Jordan, Ratnesh Lal, John Lew and Les Wilson. Together with these collaborators and additional colleagues at other institutions, we hope to gain a more complete understanding of normal neuronal development and maintenance as well as what goes wrong in neurodegenerative disease.