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.
Subject(s)
Caenorhabditis elegans Proteins/genetics , Forkhead Box Protein O3/genetics , Forkhead Transcription Factors/genetics , Huntingtin Protein/genetics , Huntington Disease/drug therapy , Aging/drug effects , Aging/genetics , Animals , Animals, Genetically Modified , Caenorhabditis elegans/drug effects , Caenorhabditis elegans/genetics , Drug Evaluation, Preclinical , Gene Expression Regulation/drug effects , Gene Knock-In Techniques , Humans , Huntington Disease/genetics , Huntington Disease/pathology , Lithium Chloride/administration & dosage , Mice , Neurons/drug effects , Neurons/pathology , Pregnenolone/administration & dosage , Quercetin/administration & dosage , Quercetin/analogs & derivativesABSTRACT
Huntington's disease (HD), an incurable neurodegenerative disorder, has a complex pathogenesis including protein aggregation and the dysregulation of neuronal transcription and metabolism. Here, we demonstrate that inhibition of sirtuin 2 (SIRT2) achieves neuroprotection in cellular and invertebrate models of HD. Genetic or pharmacologic inhibition of SIRT2 in a striatal neuron model of HD resulted in gene expression changes including significant down-regulation of RNAs responsible for sterol biosynthesis. Whereas mutant huntingtin fragments increased sterols in neuronal cells, SIRT2 inhibition reduced sterol levels via decreased nuclear trafficking of SREBP-2. Importantly, manipulation of sterol biosynthesis at the transcriptional level mimicked SIRT2 inhibition, demonstrating that the metabolic effects of SIRT2 inhibition are sufficient to diminish mutant huntingtin toxicity. These data identify SIRT2 inhibition as a promising avenue for HD therapy and elucidate a unique mechanism of SIRT2-inhibitor-mediated neuroprotection. Furthermore, the ascertainment of SIRT2's role in regulating cellular metabolism demonstrates a central function shared with other sirtuin proteins.
Subject(s)
Brain/metabolism , Gene Expression Regulation/drug effects , Huntington Disease/prevention & control , Neuroprotective Agents/pharmacology , Sirtuin 2/antagonists & inhibitors , Sterol Regulatory Element Binding Protein 2/metabolism , Sterols/biosynthesis , Analysis of Variance , Animals , Blotting, Western , Caenorhabditis elegans , Drosophila , Gene Expression Profiling , Immunohistochemistry , Mice , Microscopy, ConfocalABSTRACT
We report that Sir2 activation through increased sir-2.1 dosage or treatment with the sirtuin activator resveratrol specifically rescued early neuronal dysfunction phenotypes induced by mutant polyglutamines in transgenic Caenorhabditis elegans. These effects are dependent on daf-16 (Forkhead). Additionally, resveratrol rescued mutant polyglutamine-specific cell death in neuronal cells derived from HdhQ111 knock-in mice. We conclude that Sir2 activation may protect against mutant polyglutamines.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Caenorhabditis elegans Proteins/metabolism , Caenorhabditis elegans/physiology , Membrane Glycoproteins/physiology , Membrane Transport Proteins/physiology , Nerve Tissue Proteins/physiology , Neurons/physiology , Peptides/toxicity , Sirtuins/metabolism , Stilbenes/pharmacology , Transcription Factors/metabolism , Angiogenesis Inhibitors/pharmacology , Animals , Animals, Genetically Modified , Caenorhabditis elegans/genetics , Caenorhabditis elegans Proteins/genetics , Forkhead Transcription Factors , Homozygote , Membrane Glycoproteins/genetics , Membrane Transport Proteins/genetics , Mice , Mice, Mutant Strains , Nerve Tissue Proteins/genetics , Neurons/cytology , Resveratrol , Serotonin Plasma Membrane Transport Proteins , Sirtuins/genetics , Transcription Factors/geneticsABSTRACT
The identification of disease genes for several neurodegenerative illnesses has allowed for the development of disease models in experimental organisms. We discuss our approach to studying Huntington's disease, the best characterized of the polyglutamine (polyQ) expansion disorders. We have developed a system in Caenorhabditis elegans to study the effects of (polyQ)-dependent neuronal dysfunction at the resolution of two neurons in screening for genetic and pharmacological suppression. Our data suggest that C. elegans might be instructive in searching for targets and active compounds against polyglutamine neuronal toxicity.
