Huntington’s disease and striatal signaling

Roze, Emmanuel; Cahill, Emma; Martin, Elodie; Bonnet, Cécilia; Vanhoutte, Peter; Bétuing, Sandrine; Caboche, Jocelyne

doi:10.3389/fnana.2011.00055

Cited by 35 publications

(28 citation statements)

References 289 publications

(347 reference statements)

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“…Huntington’s disease (HD) is a progressive autosomal dominant disease characterized by early hyperkinetic movements and behavioral changes (Roze et al, 2011 ). HD patients carry an expanded CAG-repeat in exon 1 of the IT15/HTT gene that yields an elongated polyglutamine stretch in the N-terminal domain of the huntingtin (htt) protein (Bates, 2005 ).…”

Section: Introductionmentioning

confidence: 99%

Impaired TrkB Signaling Underlies Reduced BDNF-Mediated Trophic Support of Striatal Neurons in the R6/2 Mouse Model of Huntington’s Disease

Nguyen

Rymar

Sadikot

2016

Front. Cell. Neurosci.

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The principal projection neurons of the striatum are critically dependent on an afferent supply of brain derived neurotrophic factor (BDNF) for neurotrophic support. These neurons express TrkB, the cognate receptor for BDNF, which activates signaling pathways associated with neuronal survival and phenotypic maintenance. Impairment of the BDNF-TrkB pathway is suspected to underlie the early dysfunction and prominent degeneration of striatal neurons in Huntington disease (HD). Some studies in HD models indicate that BDNF supply is reduced, while others suggest that TrkB signaling is impaired earlier in disease progression. It remains important to determine whether a primary defect in TrkB signaling underlies reduced neurotrophic support and the early vulnerability of striatal neurons in HD. Using the transgenic R6/2 mouse model of HD we found that prior to striatal degeneration there are early deficits in striatal protein levels of activated phospho-TrkB and the downstream-regulated protein DARPP-32. In contrast, total-TrkB and BDNF protein levels remained normal. Primary neurons cultured from R6/2 striatum exhibited reduced survival in response to exogenous BDNF applications. Moreover, BDNF activation of phospho-TrkB and downstream signal transduction was attenuated in R6/2 striatal cultures. These results suggest that neurotrophic support of striatal neurons is attenuated early in disease progression due to defects in TrkB signal transduction in the R6/2 model of HD.

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Section: Introductionmentioning

confidence: 99%

Impaired TrkB Signaling Underlies Reduced BDNF-Mediated Trophic Support of Striatal Neurons in the R6/2 Mouse Model of Huntington’s Disease

Nguyen

Rymar

Sadikot

2016

Front. Cell. Neurosci.

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“…HD is caused by the expansion of a polyglutamine stretch in the huntingtin (HTT) protein [ 3 ]. Mutant huntingtin (mHTT) gains toxic function [ 4 – 15 ], primarily in medium spiny neurons (MSNs) [ 16 ], with aberrant interactions in several pathways, including gene expression, oxidative stress, mitochondrial function, energy metabolism, Ca 2+ homeostasis and signalling. mHTT is ubiquitously expressed and there is growing evidence that the mutant protein causes cytotoxicity not only in the central nervous system but also in the peripheral tissue of patients with HD [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Evaluating the SERCA2 and VEGF mRNAs as Potential Molecular Biomarkers of the Onset and Progression in Huntington’s Disease

et al. 2015

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Abnormalities of intracellular Ca2+ homeostasis and signalling as well as the down-regulation of neurotrophic factors in several areas of the central nervous system and in peripheral tissues are hallmarks of Huntington’s disease (HD). As there is no therapy for this hereditary, neurodegenerative fatal disease, further effort should be made to slow the progression of neurodegeneration in patients through the definition of early therapeutic interventions. For this purpose, molecular biomarker(s) for monitoring disease onset and/or progression and response to treatment need to be identified. In the attempt to contribute to the research of peripheral candidate biomarkers in HD, we adopted a multiplex real-time PCR approach to analyse the mRNA level of targeted genes involved in the control of cellular calcium homeostasis and in neuroprotection. For this purpose we recruited a total of 110 subjects possessing the HD mutation at different clinical stages of the disease and 54 sex- and age-matched controls. This study provides evidence of reduced transcript levels of sarco-endoplasmic reticulum-associated ATP2A2 calcium pump (SERCA2) and vascular endothelial growth factor (VEGF) in peripheral blood mononuclear cells (PBMCs) of manifest and pre-manifest HD subjects. Our results provide a potentially new candidate molecular biomarker for monitoring the progression of this disease and contribute to understanding some early events that might have a role in triggering cellular dysfunctions in HD.

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“…It still remains to be established whether the mutant Htt aggregates are incidental, pathogenic, or neuroprotective. Expansion of polyglutamine in Htt produces by itself multiple cellular dysfunctions, including excitotoxicity, altered mitochondrial functions, axonal transport deficit, altered proteasome activity, and gene dysregulation, that were extensively described in other reviews (8, 13). Among these alterations, transcriptional dysregulation occurs at early neuropathological stages in HD and seems to be seminal in the neuropathological process.…”

Section: Introductionmentioning

confidence: 94%

“…(8) for review]. Chorea is the most characteristic movement disorder of HD and is characterized by brief, involuntary, abnormal movements, which appear unpredictably in all the parts of the body.…”

Section: Introductionmentioning

confidence: 99%

Multiple Aspects of Gene Dysregulation in Huntington’s Disease

2013

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Huntington’s Disease (HD) is a genetic neurodegenerative disease caused by a CAG expansion in the gene encoding Huntingtin (Htt). It is characterized by chorea, cognitive, and psychiatric disorders. The most affected brain region is the striatum, and the clinical symptoms are directly correlated to the rate of striatal degeneration. The wild-type Htt is a ubiquitous protein and its deletion is lethal. Mutated (expanded) Htt produces excitotoxicity, mitochondrial dysfunctions, axonal transport deficit, altered proteasome activity, and gene dysregulation. Transcriptional dysregulation occurs at early neuropathological stages in HD patients. Multiple genes are dysregulated, with overlaps of altered transcripts between mouse models of HD and patient brains. Nuclear localization of Exp-Htt interferes with transcription factors, co-activators, and proteins of the transcriptional machinery. Another key mechanism described so far, is an alteration of cytoplasmic retention of the transcriptional repressor REST, which is normally associated with wild-type Htt. As such, Exp-Htt causes alteration of transcription of multiple genes involved in neuronal survival, plasticity, signaling, and mitochondrial biogenesis and respiration. Besides these transcriptional dysregulations, Exp-Htt affects the chromatin structure through altered post-translational modifications (PTM) of histones and methylation of DNA. Multiple alterations of histone PTM are described, including acetylation, methylation, ubiquitylation, polyamination, and phosphorylation. Exp-Htt also affects the expression and regulation of non-coding microRNAs (miRNAs). First multiple neural miRNAs are controlled by REST, and dysregulated in HD, with concomitant de-repression of downstream mRNA targets. Second, Exp-Htt protein or RNA may also play a major role in the processing of miRNAs and hence pathogenesis. These pleiotropic effects of Exp-Htt on gene expression may represent seminal deleterious effects in the pathogenesis of HD.

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Huntington’s disease and striatal signaling

Cited by 35 publications

References 289 publications

Impaired TrkB Signaling Underlies Reduced BDNF-Mediated Trophic Support of Striatal Neurons in the R6/2 Mouse Model of Huntington’s Disease

Impaired TrkB Signaling Underlies Reduced BDNF-Mediated Trophic Support of Striatal Neurons in the R6/2 Mouse Model of Huntington’s Disease

Evaluating the SERCA2 and VEGF mRNAs as Potential Molecular Biomarkers of the Onset and Progression in Huntington’s Disease

Multiple Aspects of Gene Dysregulation in Huntington’s Disease

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