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 pathogenesis appears to involve the production of mutated N-terminal htt, cytoplasmic and nuclear aggregation of htt, and abnormal activity of htt interactor proteins essential to neuronal survival. Before cell death, neuronal dysfunction may be an important step of HD pathogenesis. To explore polyQ-mediated neuronal toxicity, we expressed the first 57 amino acids of human htt containing normal [19 Gln residues (Glns)] and expanded (88 or 128 Glns) polyQ fused to fluorescent marker proteins in the six touch receptor neurons of Caenorhabditis elegans. Expanded polyQ produced touch insensitivity in young adults. Noticeably, only 28 +/- 6% of animals with 128 Glns 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 Glns were observed. In contrast, significant deposits and morphological abnormalities in PLM cell axons were observed with expanded polyQ (128 Glns) and partially correlated with touch insensitivity. PLM cell death was not detected in young or old adults. These animals indicate that significant neuronal dysfunction without cell death may be induced by expanded polyQ and may correlate with axonal insults, and not cell body aggregates. These animals also provide a suitable model to perform in vivo suppression of polyQ-mediated neuronal dysfunction.
Parker
J A
JA
Laboratory of Genomic Biology, Fondation Jean Dausset Centre d'Etude du Polymorphisme Humain, 75010 Paris, France.
Connolly
J B
JB
Wellington
C
C
Hayden
M
M
Dausset
J
J
Neri
C
C
D000818:Animals; D030801:Animals, Genetically Modified; D001369:Axons; D017173:Caenorhabditis elegans / Q000166:cytology / Q000378:metabolism*; D016923:Cell Death; D049452:Green Fluorescent Proteins; D006816:Huntington Disease / Q000378:metabolism / Q000473:pathology; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008856:Microscopy, Fluorescence; D009475:Neurons, Afferent / Q000502:physiology*; D010455:Peptides / Q000378:metabolism*
D008164:Luminescent Proteins; D010455:Peptides; D049452:Green Fluorescent Proteins; C097188:polyglutamine