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.
Highlights
Key lifespan modulators such as the FOXO (Forkhead box O), AMPK (AMP-activated protein kinase) and sirtuin (Sir2) proteins are central regulator of cellular homeostasis and survival mechanisms in response to stress[1, 2]
Neuroprotection in 128Q nematodes is dependent on daf-16/ FOXO interactors that may be individually used by these compounds as biological targets, including ptl-1/microtubule-associated protein (MAP) for MAP4343, daf-12/NR1H3 for 17ßE2, sir 2.1/SIRT1 for isoquercitrin and bar-1/ß-catenin for lithium chloride (LiCl)
The right panel shows that 17ßE2 protection against axonal dystrophy is lost in 128Q nematodes with loss-of-function of daf-12 or bar-1. (G) The left panel shows that neuroprotection by MAP4343 (100 μM and 33.3 μM) is primarily dependent on daf-16/FOXO and ptl-1/MAP
Summary
Transactivate DAF-1214 and regulate aging[15]. Here, we hypothesized that neurosteroids may promote the function of vulnerable neurons in neurodegenerative diseases and that neuroprotection by these compounds may involve stress response and cell survival pathways. Isoquercitrin reduces the stress vulnerability of mutant Htt mouse striatal cells (Fig. 3C), with no effect on the expression levels of full length huntingtin (Fig. 3D) These data suggest that medicinal chemistry studies can successfully identify families of neuroprotective compounds that may engage FOXO signalling while presenting a chemical structure that is suggestive of active drug properties. We previously reported that AMPK activators such as metformin may be dependent on daf-16/FOXO for neuroprotection in 128Q nematodes[23] (Fig. 4A) These data raise the possibility that multiple compound families might use a stress response network centered onto genes that function upstream or downstream to FOXO and its co-factors for promoting neuronal compensation in HD. These data suggest that chemical compounds involving a daf-16/FOXO-interaction network for neuroprotection could constitute bona fide drugs for promoting stress reponse and neuronal compensation in HD
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