Download Polarized expression of Caspr molecules in neurons

POSTER PRESENTATION
Suppression of toxicity by AKT and chaperone proteins differs in the brain in Drosophila models of
Huntington’s disease
Jean-Charles Liévens1, Magali Iché2, Monique Laval1, Catherine Faivre-Sarrailh1 and Serge Birman2
1
Neurobiologie des Interactions Cellulaires et Neurophysiopathologie, UMR 6184, Marseille
2
IBDML, campus de Luminy, Marseille
Huntington's disease (HD) is a late onset heritable neurodegenerative disorder caused by expansion of a polyglutamine
(polyQ) sequence in the protein Huntingtin (Htt). It is assumed that neuronal and glial functional impairments precede
the neurodegeneration and are primary responsible for early phases of HD pathogenesis. Epidermal growth factor
(EGF) signalling pathway is a key actor regulating neuron-glia cross talk. The presence of mutant Htt inhibits EGF
signal transduction and the ensuing activation of protein kinase B (AKT) and extracellular-signal regulated proteine
kinase (ERK). In recent years, a number of candidate rescuer genes have been identified in Drosophila models of polyQ
diseases. They include chaperone proteins such as HSP40 and HSP70 and proteins regulating apoptosis. In most cases,
analysis was performed on the Drosophila eye phenotype and only some of rescuer genes were further tested on
neuronal pathology; none of them were evaluated on glial alterations.
Here we used a genetic approach in HD Drosophila models to compare the potential benefits of AKT/ERK kinases with
protein chaperones in the eye and brain. The presence of mutant Htt in the fly eye resulted in pigmentary cell and
photoreceptor loss. When mutant Htt was selectively expressed in neurons or glia, Drosophila showed progressive
locomotor deficits and reduced lifespan. We found that both AKT and HSP70 alleviated the mutant Htt-induced cell
toxicity in the eye. Overexpression of AKT or HSP70 significantly decreased eye pigmentation and photoreceptor loss.
In contrast, the effects of AKT and HSP70 differ when they were expressed in the brain. HSP70 but not AKT rescued
neuronal degeneration in mushroom bodies (central brain area), decreased locomotor deficits and prolonged the lifespan
of flies expressing mutant Htt in neurons or glia. ERK expression induced deleterious effects and did not improve the
HD phenotype in the eye and brain.
We conclude that increasing AKT delays mutant Htt-induced apoptosis in the eye but likely not nervous cell
dysfunction in brain. In contrast, chaperone proteins prevent early deleterious effects of mutant Htt.