Enhanced Neuronal Glucose Transporter Expression Reveals Metabolic Choice in a HD Drosophila Model

Abstract

Huntington’s disease is a neurodegenerative disorder caused by toxic insertions of polyglutamine residues in the Huntingtin protein and characterized by progressive deterioration of cognitive and motor functions. Altered brain glucose metabolism has long been suggested and a possible link has been proposed in HD. However, the precise function of glucose transporters was not yet determined. Here, we report the effects of the specifically-neuronal human glucose transporter expression in neurons of a Drosophila model carrying the exon 1 of the human huntingtin gene with 93 glutamine repeats (HQ93). We demonstrated that overexpression of the human glucose transporter in neurons ameliorated significantly the status of HD flies by increasing their lifespan, reducing their locomotor deficits and rescuing eye neurodegeneration. Then, we investigated whether increasing the major pathways of glucose catabolism, glycolysis and pentose-phosphate pathway (PPP) impacts HD. To mimic increased glycolytic flux, we overexpressed phosphofructokinase (PFK) which catalyzes an irreversible step in glycolysis. Overexpression of PFK did not affect HQ93 fly survival, but protected from photoreceptor loss. Overexpression of glucose-6-phosphate dehydrogenase (G6PD), the key enzyme of the PPP, extended significantly the lifespan of HD flies and rescued eye neurodegeneration. Since G6PD is able to synthesize NADPH involved in cell survival by maintenance of the redox state, we showed that tolerance to experimental oxidative stress was enhanced in flies co-expressing HQ93 and G6PD. Additionally overexpressions of hGluT3, G6PD or PFK were able to circumvent mitochondrial deficits induced by specific silencing of genes necessary for mitochondrial homeostasis. Our study confirms the involvement of bioenergetic deficits in HD course; they can be rescued by specific expression of a glucose transporter in neurons. Finally, the PPP and, to a lesser extent, the glycolysis seem to mediate the hGluT3 protective effects, whereas, in addition, the PPP provides increased protection to oxidative stress.

Glial lipid droplets and neurodegeneration in a Drosophila model of complex I deficiency

“…As previously described, knockdown of ND23 in neurons causes shortened lifespan (Besson, Alegría, Garrido-Gerter, Barros, & Li evens, 2015). As previously described, knockdown of ND23 in neurons causes shortened lifespan (Besson, Alegría, Garrido-Gerter, Barros, & Li evens, 2015).…”

“…Indeed, we previously observed that the overexpression of the human glucose transporter hGluT3 is able to suppress the lethality induced by the ND23 RNAi (Besson et al, 2015). Indeed, we previously observed that the overexpression of the human glucose transporter hGluT3 is able to suppress the lethality induced by the ND23 RNAi (Besson et al, 2015).…”

Metabolic Reprogramming in Astrocytes Distinguishes Region-Specific Neuronal Susceptibility in Huntington Mice

“…We show that FAs are used to restore OCR only when glucose is low in the sensitive STR (Figure 6). Indeed, overexpression of glucose-6-phosphate dehydrogenase, the major enzyme for the pentose phosphate pathway (PPP) (Legan et al, 2008), or overexpression of a glucose transporter (Besson et al, 2015) extends lifetime in flies expressing 93 glutamine repeats. The CBL in HdhQ(150/150) animals is replete with amino acid precursors for these pathways and this region is more resistant to toxicity.…”

Neuroprotection by glucose‐6‐phosphate dehydrogenase and the pentose phosphate pathway

“…Overexpression of G6PD extended lifespan of transgenic HD fly significantly 99 Drosophila transgenic model Overexpression of G6PD in Drosophila neurons delayed proteostasis decline with age and extend lifespan 21 Transgenic mice with moderate expression of G6PD Moderate transgenic overexpression of G6PD in mice extended healthspan and median lifespan of females 24 Development of a G6PD agonist G6PD agonist AG1 effectively activated G6PD and reduced oxidative stress in G6PD-deficient human fibroblasts and zebrafish embryo 22 Abbreviations: G6PD, glucose-6-phosphate dehydrogenase; OGD, oxygen-glucose deprivation; PPP, pentose phosphate pathway. TANG | 14291…”

“…A more direct indication of a beneficial effect of G6PD in HD is demonstrated by a Drosophila transgenic model. For flies carrying the exon 1 of the human huntingtin gene with 93 glutamine repeats (HQ93), overexpression of G6PD was shown to significantly increased lifespan and reduced eye neurodegeneration …”