Cytoplasmic aggregates trap polyglutamine-containing proteins and block axonal transport in a Drosophila model of Huntington's disease

WCM Lee, M Yoshihara… - Proceedings of the …, 2004 - National Acad Sciences
WCM Lee, M Yoshihara, JT Littleton
Proceedings of the National Academy of Sciences, 2004National Acad Sciences
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 generated Drosophila transgenic strains
expressing human huntingtin cDNAs encoding pathogenic (Htt-Q128) or nonpathogenic …
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 generated Drosophila transgenic strains expressing human huntingtin cDNAs encoding pathogenic (Htt-Q128) or nonpathogenic proteins (Htt-Q0). Whereas expression of Htt-Q0 has no discernible effect on behavior, lifespan, or neuronal morphology, pan-neuronal expression of Htt-Q128 leads 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 disruption of axonal transport and accumulation of aggregates at synapses. 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. Our findings indicate that nonnuclear events induced by cytoplasmic huntingtin aggregation play a central role in the progressive neurodegeneration observed in Huntington's disease.
National Acad Sciences