Research

Beginning with a long-standing interest in molecular mechanisms underlying the normal development and maintenance of the nervous system, our work has evolved to include a major effort to understand neurodegenerative diseases such as Alzheimer's, FTDP-17 and Progressive Supranuclear Palsy. Our investigations focus upon the normal and pathological action of the microtubule associated protein, tau. Normally, this tightly regulated protein controls microtubule growing and shortening, thereby regulating the numerous essential functions performed by microtubules such as axonal transport. On the other hand, tau dysfunction has long been associated with Alzheimer's disease and related dementias. Recent genetic analyses have demonstrated that mutations affecting either the primary structure or tau, or regulation of its action, can cause neuronal cell death and dementia. Unfortunately, the underlying molecular mechanisms by which tau destroys neurons remains very poorly understood.

Our efforts to understand normal and pathological tau action employ a wide range of strategies and technologies, including protein biochemistry, molecular cell biology, biophysics and bioengineering. Many of these efforts are collaborative with colleagues here at UCSB and elsewhere. We seek to understand precise mechanistic details by which tau regulates microtubule behavior and neuronal cell biology, integrating high resolution in vitro biochemical and biophysical analyses with investigations in cells. Among our most recent efforts are analyses examining the roles of tau in axonal transport under normal and pathological conditions, the possible roles of tau fragmentation in the onset of disease, the possible role of tau oligomerization in normal and pathological tau action and the combinatorial effects of multiple phosphorylation upon the regulation of tau action. Together with our many collaborators, we hope to gain a more complete understanding of normal neuronal development and maintenance as well as what goes wrong in neurodegenerative disease.