Genetic and Pharmacological Suppression of Polyglutamine-Dependent Neuronal Dysfunction in &lt;I&gt;Caenorhabditis elegans&lt;/I&gt;

Parker, J. Alex; Holbert, Sébastien; Lambert, Emmanuel; Abderrahmane, Salima; Néri, Christian

doi:10.1385/jmn:23:1-2:061

Cited by 19 publications

(17 citation statements)

References 64 publications

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“…In addition, the synaptic vesicle protein synaptobrevin significantly accumulated at the nerve terminals of hipr-1 mutant nematode worms, similar to what it happens in nematode worms with mutations in endocytic proteins such as AP180 (clathrin coat-assembly protein 180) and endophilinA [36]. Interestingly, behavioral deficits in nematode worms expressing 128Q-htt become aggravated upon genetic removal of hipr-1 or other endocytic proteins [37]. Thus hipr-1 might have a role in presynaptic alterations in HD.…”

Section: Synaptic Proteins In Hdmentioning

confidence: 52%

Presynaptic dysfunction in Huntington's disease

Rozas

Gómez‐Sánchez

Tomás-Zapico

et al. 2010

Biochemical Society Transactions

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HD (Huntington's disease) is produced by the expression of mutant forms of the protein htt (huntingtin) containing a pathologically expanded poly-glutamine repeat. For unknown reasons, in HD patients and HD mouse models, neurons from the striatum and cerebral cortex degenerate and lead to motor dysfunction and dementia. Synaptic transmission in those neurons becomes progressively altered during the course of the disease. However, the relationship between synaptic dysfunction and neurodegeneration in HD is not yet clear. Are there early specific functional synaptic changes preceding symptoms and neurodegeneration? What is the role of those changes in neuronal damage? Recent experiments in a Drosophila model of HD have showed that abnormally increased neurotransmitter release might be a leading cause of neurodegeneration. In the present review, we summarize recently described synaptic alterations in HD animal models and discuss potential underlying molecular mechanisms.

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Section: Synaptic Proteins In Hdmentioning

confidence: 52%

Presynaptic dysfunction in Huntington's disease

Rozas

Gómez‐Sánchez

Tomás-Zapico

et al. 2010

Biochemical Society Transactions

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“…While FOXO3 may promote apoptosis in dopaminergic neurons of the adult rat substantia nigra pars compacta subjected to acute oxidative stress, FOXO3 may protect these neurons against human α-synuclein expression 9 . FOXO factors also show protective effects in several models of neuronal dysfunction and cell vulnerability in HD 6, 18, 23, 48 . From a therapeutic prospective, this suggests that FOXO protection is relevant to the phases of neurodegenerative disease processes during which neurons retain the capacity to compensate for cellular stress and maintain function.…”

Section: Discussionmentioning

confidence: 99%

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

Farina

Lambert

Commeau

et al. 2017

Sci Rep

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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.

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“…In lower organisms, these have taken the form of genetic screens to identify genes that modify some specific phenotype in an engineered animal model. For example, screens in yeast, Caenorhabditis elegans and Drosophila melanogaster expressing an introduced fragment from human huntingtin consisting largely of polyglutamine have yielded a number of modifiers of the effects of this fragment [47-50]. Indeed, in the Drosophila system, the orthologs of proteins that interact physically with human huntingtin have been suggested to be over-represented among modifiers.…”

Section: Genetic Modifiers - the Unbiased Approachmentioning

confidence: 99%

Huntington's disease: the case for genetic modifiers

2009

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For almost three decades, Huntington's disease has been a prototype for the application of genetic strategies to human disease. HD, the Huntington's disease gene, was the first autosomal defect mapped using only DNA markers, a finding in 1983 that helped to spur similar studies in many other disorders and contributed to the concept of the human genome project. The search for the genetic defect itself pioneered many mapping and gene-finding technologies, and culminated in the identification of the HD gene, its mutation and its novel protein product in 1993. Since that time, extensive investigations into the pathogenic mechanism have utilized the knowledge of the disease gene and its defect but, with notable exceptions, have rarely relied for guidance on the genetic findings in human patients to interpret the relevance of findings in non-human model systems. However, the human patient still has much to teach us through a detailed analysis of genotype and phenotype. Such studies have implicated the existence of genetic modifiers - genes whose natural polymorphic variation contributes to altering the development of Huntington's disease symptoms. The search for these modifiers, much as the search for the HD gene did in the past, offers to open new entrées into the process of Huntington's disease pathogenesis by unlocking the biochemical changes that occur many years before diagnosis, and thereby providing validated target proteins and pathways for development of rational therapeutic interventions.

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Genetic and Pharmacological Suppression of Polyglutamine-Dependent Neuronal Dysfunction in <I>Caenorhabditis elegans</I>

Cited by 19 publications

References 64 publications

Presynaptic dysfunction in Huntington's disease

Presynaptic dysfunction in Huntington's disease

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

Huntington's disease: the case for genetic modifiers

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