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Human Molecular Genetics Advance Access published online on January 27, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi067
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Human Molecular Genetics © Oxford University Press 2005; all rights reserved

Article

Expanded polyglutamine peptides disrupt EGF receptor signaling and glutamate transporter expression in Drosophila

Jean-Charles Liévens 1, Thomas Rival 1, Magali Iché 1, Hervé Chneiweiss 2, and Serge Birman 1*

1 Laboratoire de Génétique et Physiologie du Développement, Developmental Biology Institute of Marseille, CNRS-INSERM-Université de la Méditerranée, Campus de Luminy, Case 907, F-13288 Marseille Cedex 9, France
2 Inserm U114, Collège de France, 11 place Marcellin-Berthelot, 75231 Paris Cedex 05, France

* To whom correspondence should be addressed.
Serge Birman, E-mail: birman{at}ibdm.univ-mrs.fr


  Abstract

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.


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