09.1990–09.1995 Ph.D., Duke University Medical Center

10.1995–09.1997 Postdoctoral Fellow, University College London

10.1997–06.2000 Postdoctoral Fellow, University of California, San Francisco (UCSF)

07.2000–05.2006 Assistant Investigator/Assistant Professor, Gladstone/UCSF

06.2006–01.2010 Associate Investigator/Associate Professor, Gladstone/UCSF

02.2010–present Professor, Department of Neurology, UMMS

Understanding Frontotemporal Dementia and Neuronal microRNAs

Frontotemporal dementia (FTD), a major clinical syndrome of frontotemporal lobar degeneration (FTLD), is an age-dependent neurodegenerative condition associated with focal atrophy of the frontal and/or temporal lobes. It is often associated with parkinsonism or amyotrophic lateral sclerosis (ALS), and is recognized now as the most common form of dementia before the age of 60. Unfortunately, the molecular pathogenesis of FTD remains largely unknown and effective treatments are not available. Recent exciting advances indicate that several proteins are involved in the pathogenesis of FTD and its related disorders, including CHMP2B, progranulin, TDP-43, FUS, and c9ORF72. How these mutant proteins cause or contribute to neurodegeneration remains poorly defined.

A few years ago, we cloned a novel Drosophila gene called shrub, which encodes a key component of ESCRT-III and regulates dendritic morphogenesis. In cultured cortical neurons, we found that dysfunctional ESCRT-III, lacking essential components (such as mSnf7-2, one of the mouse homologs of Shrub) or containing ectopically expressed FTD3-associated mutant CHMP2B, causes dendritic retraction, autophagosome accumulation and eventual neurodegeneration. We recently also showed that inhibiting induction of autophagy delays neuronal cell loss caused by mutant CHMP2B. Moreover, through an unbiased genetic screen in a novel fly model of FTD3, we identified the Toll pathway as a major target of CHMP2B toxicity in vivo. Other modifier genes remain to be further characterized.

Over the next a few years, we will use a combination of molecular, cellular, genetic, and behavioral approaches to further dissect the pathogenic mechanisms involving mutant CHMP2B and some other FTD/ALS disease genes, and identify common underlying pathways as potential targets for therapeutic interventions. To this end, multiple experimental systems will be utilized, including Drosophila, mouse models, and patient-specific induced pluripotent stem (iPS) cells.

Another major research interest in our laboratory is the microRNA pathway. The roles of specific microRNAs in neuronal development and neurodegeneration in fly and mammalian model systems will be investigated in detail.