Expanded polyglutamine peptides disrupt EGF receptor signaling and glutamate transporter expression in Drosophila.
Huntington's disease (HD) is a late onset heritable neurodegenerative disorder caused by expansion of a polyglutamine (polyQ) sequence in the protein huntingtin (Htt). Transgenic models in mice have suggested that the motor and cognitive deficits associated to this disease are triggered by extended neuronal and possibly glial dysfunction, whereas neuronal death occurs late and selectively. Here, we provide in vivo evidence that expanded polyQ peptides antagonize epidermal growth factor receptor (EGFR) signaling in Drosophila glia. We targeted the expression of the polyQ-containing domain of Htt or an extended polyQ peptide alone in a subset of Drosophila glial cells, where the only fly glutamate transporter, dEAAT1, is detected. This resulted in formation of nuclear inclusions, progressive decrease in dEAAT1 transcription and shortened adult lifespan, but no significant glial cell death. We observed that brain expression of dEAAT1 is normally sustained by the EGFR-Ras-extracellular signal-regulated kinase (ERK) signaling pathway, suggesting that polyQ could act by antagonizing this pathway. We found that the presence of polyQ peptides indeed abolished dEAAT1 upregulation by constitutively active EGFR and potently inhibited EGFR-mediated ERK activation in fly glial cells. Long polyQ also limited the effect of activated EGFR on Drosophila eye development. Our results further indicate that the polyQ acts at an upstream step in the pathway, situated between EGFR and ERK activation. This suggests that disruption of EGFR signaling and ensuing glial cell dysfunction could play a direct role in the pathogenesis of HD and other polyQ diseases in humans.
Liévens
Jean-Charles
JC
CNRS-INSERM-Université de la Méditerranée, Marseille, France.
Rival
Thomas
T
Iché
Magali
M
Chneiweiss
Hervé
H
Birman
Serge
S
D000818:Animals; D004331:Drosophila melanogaster / Q000235:genetics* / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D027341:Excitatory Amino Acid Transporter 1 / Q000235:genetics* / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005123:Eye / Q000378:metabolism; D017930:Genes, Reporter; D018698:Glutamic Acid / Q000378:metabolism*; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism; D008136:Longevity / Q000235:genetics / Q000502:physiology; D009457:Neuroglia / Q000378:metabolism; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D015854:Up-Regulation; D018631:ras Proteins / Q000378:metabolism
D027341:Excitatory Amino Acid Transporter 1; D010455:Peptides; C097188:polyglutamine; D018698:Glutamic Acid; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins