Daf-2 Signaling Modifies Mutant SOD1 Toxicity in C. elegans

Roswell Park Cancer Institute, United States of America
PLoS ONE (Impact Factor: 3.23). 03/2012; 7(3):e33494. DOI: 10.1371/journal.pone.0033494
Source: PubMed


The DAF-2 Insulin/IGF-1 signaling (IIS) pathway is a strong modifier of Caenorhabditis elegans longevity and healthspan. As aging is the greatest risk factor for developing neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (ALS), we were interested in determining if DAF-2 signaling modifies disease pathology in mutant superoxide dismutase 1 (SOD1) expressing C. elegans. Worms with pan-neuronal G85R SOD1 expression demonstrate significantly impaired locomotion as compared to WT SOD1 expressing controls and they develop insoluble SOD1 aggregates. Reductions in DAF-2 signaling, either through a hypomorphic allele or neuronally targeted RNAi, decreases the abundance of aggregated SOD1 and results in improved locomotion in a DAF-16 dependant manner. These results suggest that manipulation of the DAF-2 Insulin/IGF-1 signaling pathway may have therapeutic potential for the treatment of ALS.

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    • "This provides the exciting opportunity to utilize age-modified animals to enrich for gene candidates involved in neurodegenerative disease processes. Among proteotoxicity models in worms, reduced IIS has demonstrated protection against amyloid-b (Ab), polyglutamine-repeat (polyQ) proteins, and SOD-1 (Morley et al., 2002; Cohen et al., 2006; Boccitto et al., 2012). Similarly, expression of insulin-degrading enzyme in Drosophila suppresses Ab neurotoxicity (Tsuda et al., 2010). "
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    ABSTRACT: Neurodegenerative diseases represent an increasing burden in our aging society, yet the underlying metabolic factors influencing onset and progression remain poorly defined. The relationship between impaired IGF-1/insulin-like signaling (IIS) and lifespan extension represents an opportunity to investigate the interface of metabolism with age-associated neurodegeneration. Using data sets of established DAF-2/IIS-signaling components in Caenorhabditis elegans, we conducted systematic RNAi screens in worms to select for daf-2-associated genetic modifiers of α-synuclein misfolding and dopaminergic neurodegeneration, two clinical hallmarks of Parkinson's disease. An outcome of this strategy was the identification of GPI-1/GPI, an enzyme in glucose metabolism, as a daf-2-regulated modifier that acts independent of the downstream cytoprotective transcription factor DAF-16/FOXO to modulate neuroprotection. Subsequent mechanistic analyses using Drosophila and mouse primary neuron cultures further validated the conserved nature of GPI neuroprotection from α-synuclein proteotoxicity. Collectively, these results support glucose metabolism as a conserved functional node at the intersection of proteostasis and neurodegeneration.
    Full-text · Article · May 2014 · Cell Metabolism
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    • "This coupled with the identification of the FOXA2 association with sporadic ALS, as mentioned above implies that FOXO transcriptional regulation may be altered in ALS. In fact, the Caenorhabditis elegans FOXO3a ortholog, DAF-16 was shown to be required for lifespan extension and improved movement by reducing the toxic effects of TDP-43 (transactive response DNA binding protein 43) and SOD1 (superoxide dismutase 1) (Boccitto et al., 2012; Vaccaro et al., 2012; Zhang et al., 2011) which have both been linked to sporadic and familial forms of ALS (Sreedharan et al., 2008; Kabashi et al., 2008; Rosen et al., 1993; Jones et al., 1993). The importance of FOXO in other neurodegenerative diseases has been demonstrated in both C. elegans and elsewhere (Wong et al., 2013; Parker et al., 2012; Maiese et al., 2007; Morley et al., 2002). "
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    ABSTRACT: Exposures to high levels of environmental selenium have been associated with motor neuron disease in both animals and humans and high levels of selenite have been identified in the cerebrospinal fluid of patients with amyotrophic lateral sclerosis (ALS). We have shown previously that exposures to high levels of sodium selenite in the environment of C. elegans adult animals can induce neurodegeneration and cell loss resulting in motor deficits and death and that this is at least partially caused by a reduction in cholinergic signaling across the neuromuscular junction. Here we provide evidence that reduction in insulin/insulin-like (IIS) signaling alters response to high dose levels of environmental selenium which in turn can regulate the IIS pathway. Most specifically we show that nuclear localization and thus activation of the DAF-16/forkhead box transcription factor occurs in response to selenium exposure although this was not observed in motor neurons of the ventral cord. Yet, tissue specific expression and generalized overexpression of DAF-16 can partially rescue the neurodegenerative and behavioral deficits observed with high dose selenium exposures in not only the cholinergic, but also the GABAergic motor neurons. In addition, two modifiers of IIS signaling, PTEN (phosphatase and tensin homolog, deleted on chromosome 10) and PINK1 (PTEN-induced putative kinase 1) are required for the cellular antioxidant reduced glutathione to mitigate the selenium-induced movement deficits. Studies have suggested that environmental exposures can lead to ALS or other neurological diseases and this model of selenium-induced neurodegeneration developed in a genetically tractable organism provides a tool for examining the combined roles of genetics and environment in the neuro-pathologic disease process.
    Full-text · Article · Jan 2014 · NeuroToxicology
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    • "The IIS pathway is a key modifier of aging and the daf-2(e1370) mutants show increased lifespan in C. elegans (Kenyon et al., 1993). As aging is a common risk factor in neurodegenerative diseases, this work suggests that alteration of the IIS signaling may have therapeutic potentials for the cure of ALS (Boccitto et al., 2012). "
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    ABSTRACT: Neurodegenerative diseases which include Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington disease (HD), and others are becoming an increasing threat to human health worldwide. The degeneration and death of certain specific groups of neurons is the hallmark of these diseases. Despite the research progress in identification of several disease-related genes, the mechanisms underlying the neurodegeneration in these diseases remain unclear. Given the molecular conservation in neuronal signaling between Caenorhabditis elegans and vertebrates, increasing number of research scientists has used the nematode to study this group of diseases. This review paper will focus on the model system that has been established in Caenorhabditis elegans to investigate the pathogenetic roles of those reported disease-related genes in AD, PD, ALS, HD and others. The progress in Caenorhabditis elegans provides useful information of the genetic interactions and molecular pathways that are critical in the disease process, and may help our better understanding of the disease mechanisms and search for new therapeutics for these devastating diseases.
    Full-text · Article · Oct 2013 · Experimental Neurology
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