Wyan-Ching Mimi Lee,   2001-  

B.S. Biology, 1999  Brown University

Mimi began the lab effort to generate and characterize fly models of Huntington’s Disease.  Huntington’s disease is an autosomal dominant neurodegenerative disorder caused by expansion of a polyglutamine tract in the huntingtin protein that results in intracellular aggregate formation and neurodegeneration.  Pathways leading from polyglutamine tract expansion to disease pathogenesis remain obscure.  To elucidate how polyglutamine expansion causes neuronal dysfunction, Mimi generated Drosophila transgenic strains expressing human huntingtin cDNAs encoding pathogenic (Htt-Q128) or nonpathogenic proteins (Htt-Q0).  While expression of Htt-Q0 has no discernible effect on behavior, lifespan or neuronal morphology, pan-neuronal expression of Htt-Q128 led to progressive loss of motor coordination, decreased lifespan and time-dependent formation of huntingtin aggregates specifically in the cytoplasm and neurites.  Huntingtin aggregates sequester other expanded polyglutamine proteins in the cytoplasm and lead to synaptic aggregate accumulation and disruption of axonal transport.  In contrast, Drosophila expressing an expanded polyglutamine tract alone, or an expanded polyglutamine tract in the context of the spinocerebellar ataxia type 3 protein, display only nuclear aggregates and do not disrupt axonal trafficking.  Mimi’s  findings indicate that non-nuclear events induced by cytoplasmic huntingtin aggregation may play a central role in the progressive neurodegeneration observed in Huntington’s disease.