AKT-sensitive or insensitive pathways of toxicity in glial cells and neurons in Drosophila models of Huntington's disease.
Huntington's disease (HD) is caused by an extended polyglutamine (polyQ) tract in the Huntingtin protein. Neuronal and glial dysfunction precedes the neurodegeneration and appears to be the primary cause for the early symptoms in HD. In recent years, development of Drosophila models of polyQ-related diseases facilitated research of candidate rescuer genes. In most cases, analysis in Drosophila was performed by assessing toxicity on retinal and/or brain neurons. However, none of the potential rescuers were evaluated on glial alterations. Here we used a genetic approach in Drosophila to characterize the phenotypic effects of mutant Huntingtin (mHtt) expressed in neurons or different glia subsets and we established a sensitive assay for evaluating modifiers of glial alterations. We determined the level of cell protection ensured by activation of the AKT and ERK anti-apoptotic kinases in the retina as well as in neurons and glia of the fly brain, compared with the rescuing effects of the HSP70 chaperone. We found that both AKT and HSP70 alleviated mHtt-induced toxicity in the retina. In contrast, their protective effects differed in the brain. HSP70 rescued neurodegeneration, locomotor defects and early lethality of flies expressing mHtt in neurons or glia. AKT failed to prevent brain neuronal death and lethality of flies, but significantly improved their locomotor performance when co-expressed with mHtt in glia. ERK had no beneficial effects in the retina or brain. These results indicate that mHtt activates distinct pathways of toxicity in Drosophila, either sensitive to AKT in retinal photoreceptors and glia, or independent in brain neurons.
Liévens
Jean-Charles
JC
Neurobiologie des Interactions Cellulaires et Neurophysiopathologie, CNRS UMR 6184, Université de la Méditerranée, Institut Jean-Roche, 13916 Marseille Cedex 20, France. jean-charles.lievens@univmed.fr
Iché
Magali
M
Laval
Monique
M
Faivre-Sarrailh
Catherine
C
Birman
Serge
S
D000818:Animals; D004195:Disease Models, Animal; D004331:Drosophila melanogaster; D018840:HSP70 Heat-Shock Proteins / Q000502:physiology; D006801:Humans; D006816:Huntington Disease / Q000201:enzymology* / Q000473:pathology; D007150:Immunohistochemistry; D009043:Motor Activity; D009457:Neuroglia / Q000473:pathology*; D009474:Neurons / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012160:Retina / Q000473:pathology; D015398:Signal Transduction; D013050:Spectrometry, Fluorescence
D018840:HSP70 Heat-Shock Proteins; D051057:Proto-Oncogene Proteins c-akt