AKT-sensitive or insensitive pathways of toxicity in glial cells and neurons in Drosophila models of Huntington's disease

Abstract

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.

Pathogenesis of Huntington’s Disease: How to Fight Excitotoxicity and Transcriptional Dysregulation

“…This increase in the phosphorylated AKT is still detected at later stages of the neurodegenerative process, offering together with phospho-ERK, a mechanistic explanation to the small amount of neuronal death observed in these HD models (Figure 2). In accordance with our results, AKT prevents neuronal death induced by mhtt [174] and increasing AKT expression has beneficial effects on Drosophila models of HD [175]. Thus, on the basis of these results, it is not too daring to suggest that use of therapeutic approaches focusing on AKT prosurvival pathway could delay neuronal death in HD.…”

Neurodegeneration by polyglutamine Atrophin is not rescued by induction of autophagy

“…Toxicity upon glial expression is a common feature of several polyQ fly models 38,39 and, interestingly, a recent report shows that in Huntington Drosophila models, glial cell degeneration affects fly viability, but through a different pathway than the one involved in brain neuronal toxicity. 40 Remarkably, photorecteptors are affected by Huntingtin through the same pathway that affects the glia; however, glial cells appear to be more sensitive to expression of polyQ Atrophins in comparison with polyQ Huntingtin, which instead elicits a stronger effect when expressed in neurons.…”

PH domain leucine-rich repeat protein phosphatase 1 contributes to maintain the activation of the PI3K/Akt pro-survival pathway in Huntington's disease striatum

“…8 Accordingly, Akt prevents neuronal death induced by mhtt, 14 and increasing Akt expression has beneficial effects in Drosophila models of HD. 37,38 Furthermore, in an acute rat model of HD showing massive cell death a decrease of pAkt levels occurs before neuronal loss. 39 Here we show that Akt is still activated at late stages of the disease and that these changes are occurring in striatal medium-sized spiny projection neurons, the most affected in HD.…”