Expanded polyglutamines in Caenorhabditis elegans cause axonal abnormalities and severe dysfunction of PLM mechanosensory neurons without cell death

Huntington's disease (HD) is a dominant neurodegenerative disease caused by polyglutamine (polyQ) expansion in the protein huntingtin (htt). HD pathog enesis appears to involve the production of mutated N-terminal htt, cytopla smic and nuclear aggregation of htt, and abnormal activity of htt interacto r proteins essential to neuronal survival. Before cell death, neuronal dysf unction may be an important step of HD pathogenesis. To explore polyQ-media ted neuronal toxicity, we expressed the first 57 amino acids of human htt c ontaining normal [19 Gin residues (Gins)] and expanded (88 or 128 Gins) pol yQ fused to fluorescent marker proteins in the six touch receptor neurons o f Caenorhabditis elegans. Expanded polyQ produced touch insensitivity in yo ung adults. Noticeably, only 28 +/- 6% of animals with 128 Gins were touch sensitive in the tail, as mediated by the PLM neurons. Similar perinuclear deposits and faint nuclear accumulation of fusion proteins with 19, 88, and 128 Gins were observed. In contrast, significant deposits and morphologica l abnormalities in PLM cell axons were observed with expanded polyQ (128 Gi ns) and partially correlated with touch insensitivity. PLM cell death was n ot detected in young or old adults. These animals indicate that significant neuronal dysfunction without cell death may be induced by expanded polyQ a nd may correlate with axonal insults, and not cell body aggregates. These a nimals also provide a suitable model to perform in vivo suppression of poly Q-mediated neuronal dysfunction.