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, we have generated Drosophila transgenic strains expressing human huntingtin cDNAs encoding pathogenic or nonpathogenic proteins. While expression of nonpathogenic huntingtin has no discernible effect on behavior, lifespan or neuronal morphology, pan-neuronal expression of huntingtin containing a Q128 tract causes a 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. We propose to expand upon these studies to determine how non-nuclear events induced by cytoplasmic huntingtin aggregation may cause the progressive neurodegeneration observed in Huntington's disease. In addition, we will characterize the in vivo role of the native huntingtin protein and screen for direct suppressors of huntingtin aggregation. Together, these approaches should expand our understanding of the normal function of the huntingtin protein, as well as provide novel insights into the pathogenesis of Huntington's Disease.
| Schulte, Joost; Littleton, J Troy (2011) The biological function of the Huntingtin protein and its relevance to Huntington's Disease pathology. Curr Trends Neurol 5:65-78 |
| Wu, Chaohong; Schulte, Joost; Sepp, Katharine J et al. (2010) Automatic robust neurite detection and morphological analysis of neuronal cell cultures in high-content screening. Neuroinformatics 8:83-100 |
| Schulte, Joost; Sepp, Katharine J; Jorquera, Ramon A et al. (2010) DMob4/Phocein regulates synapse formation, axonal transport, and microtubule organization. J Neurosci 30:5189-203 |
| Zhang, Sheng; Feany, Mel B; Saraswati, Sudipta et al. (2009) Inactivation of Drosophila Huntingtin affects long-term adult functioning and the pathogenesis of a Huntington's disease model. Dis Model Mech 2:247-66 |
| Kimura, Yoko; Lee, Wyan-Ching Mimi; Littleton, J Troy (2007) Therapeutic prospects for the prevention of neurodegeneration in Huntington's disease and the polyglutamine repeat disorders. Mini Rev Med Chem 7:99-106 |
