The stress response factor daf-16/FOXO is required for multiple compound families to prolong the function of neurons with Huntington’s disease

Abstract

Helping neurons to compensate for proteotoxic stress and maintain function over time (neuronal compensation) has therapeutic potential in aging and neurodegenerative disease. The stress response factor FOXO3 is neuroprotective in models of Huntington’s disease (HD), Parkinson’s disease and motor-neuron diseases. Neuroprotective compounds acting in a FOXO-dependent manner could thus constitute bona fide drugs for promoting neuronal compensation. However, whether FOXO-dependent neuroprotection is a common feature of several compound families remains unknown. Using drug screening in C. elegans nematodes with neuronal expression of human exon-1 huntingtin (128Q), we found that 3ß-Methoxy-Pregnenolone (MAP4343), 17ß-oestradiol (17ßE2) and 12 flavonoids including isoquercitrin promote neuronal function in 128Q nematodes. MAP4343, 17ßE2 and isoquercitrin also promote stress resistance in mutant Htt striatal cells derived from knock-in HD mice. Interestingly, daf-16/FOXO is required for MAP4343, 17ßE2 and isoquercitrin to sustain neuronal function in 128Q nematodes. This similarly applies to the GSK3 inhibitor lithium chloride (LiCl) and, as previously described, to resveratrol and the AMPK activator metformin. Daf-16/FOXO and the targets engaged by these compounds define a sub-network enriched for stress-response and neuronally-active pathways. Collectively, these data highlights the dependence on a daf-16/FOXO-interaction network as a common feature of several compound families for prolonging neuronal function in HD.

A Progressive Loss of phosphoSer138-Profilin Aligns with Symptomatic Course in the R6/2 Mouse Model of Huntington’s Disease: Possible Sex-Dependent Signaling

“…Our kinome analysis of striatal tissues identified several candidate pathways (see Supplementary Figs. 5-8) including the Akt/FOXO3 pathway that is neuroprotective in HD (Farina et al 2017) and CDK2 (which we also observed in our NSC extracts, Fig. 1), thus suggesting a dysregulation of cell cycle regulatory proteins (Sang et al 2014).…”

SIRT1 is increased in affected brain regions and hypothalamic metabolic pathways are altered in Huntington disease

“…FOXO transcription factors such as FOXO1 and FOXO3 act as cellular sensors to survival signals and are increased in response to intracellular stress. mRNA levels of FOXO3 have previously been found increased in the striatum of HD patients and mice and a few studies have suggested a neuroprotective role for FOXO3 in HD . Here, we found that mRNA levels of FOXO3 were increased in both the LHA and the VMH in HD cases.…”

Protein Misfolding and ER Stress in Huntington's Disease

“…This includes many strategies, for example inhibiting mHtt cleavage by caspase 6 (Aharony et al, 2015), targeting or modulating heat shock proteins (Kampinga and Bergink, 2016; Scior et al, 2018), neurotrophic factors such as CNTF (Emerich et al, 1997), HDACs (Suelves et al, 2017), proteasome activity (Jeon et al, 2016), and mitochondrial oxidative phosphorylation (Ruetenik et al, 2016). Compounds that promote daf-16/FOXO function and in turn stimulate insulin/IGF1 signaling and extend longevity (Hesp et al, 2015), such as resveratrol, metformin and some steroids, have shown beneficial effects in C. elegans (Farina et al, 2017) and mouse HD models (Arnoux et al, 2018). Metformin also appeared protective in a statistical analysis of HD patients participating in the Enroll-HD database (Hervas et al, 2017).…”