Brain-specific factors in combination with mutant huntingtin induce gene-specific transcriptional dysregulation

Gomez, Geraldine T.; Hu, Haibei; McCaw, Elizabeth A.; Denovan‐Wright, Eileen M.

doi:10.1016/j.mcn.2005.12.004

Cited by 14 publications

(17 citation statements)

References 69 publications

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“…There is a progressive decrease in histone H3 acetylation associated with promoters down-regulated in HD (e.g., the D2 dopamine receptor promoter [123]), but these sequences have not been demonstrated to contribute to striatal-specific expression. For example, the physiologic relevance of selective down-regulation of the DARPP-32 core promoter in striatal, relative to renal, extracts [128] must be cautiously interpreted as this region of the ppp1r1b gene does not direct expression to the striatum and may actually contain repressive elements [129].…”

Section: Transcriptional Dysregulationmentioning

confidence: 99%

Huntington's Disease and the Striatal Medium Spiny Neuron: Cell-Autonomous and Non-Cell-Autonomous Mechanisms of Disease

Ehrlich

2012

Neurotherapeutics

120

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Huntington's disease is an autosomal dominant disorder caused by a mutation in the gene encoding the protein huntingtin on chromosome 4. The mutation is an expanded CAG repeat in the first exon, encoding a polyglutamine tract. If the polyglutamine tract is >40, penetrance is 100% and death is inevitable. Despite the widespread expression of huntingtin, HD has long been considered primarily as a disease of the striatum. It is characterized by selective vulnerability with dysfunction followed by death of the medium size spiny neuron. Considerable effort is being expended to determine whether striatal damage is cell-autonomous, non-cell-autonomous, requiring cell-cell and region to region communication, or both. We review data supporting both mechanisms. We also attempt to organize the data into common mechanisms that may arise outside the medium, spiny neuron, but ultimately have their greatest impact in the striatum. characterized by selective, or perhaps better described as differential [2], vulnerability with degeneration and death of the medium spiny neuron (MSN). The Gamma-aminobutyric acid (GABA)ergic MSN represents 95% of striatal neurons. They are all output neurons, with extensive intra-striatal connections with other MSNs and striatal interneurons. For the last two decades, increased attention has been paid to the pathology in the cortex (particularly in layers V and VI [3]), which contains the corticostriatal projection neurons.Prior to identification of the HTT gene, the huntingtin protein, and the nature of its mutation, it was assumed that selective neuronal vulnerability in HD would be conferred by the expression pattern of the mutated protein (polyQ-htt). As it is now apparent, htt is expressed throughout the nervous system and periphery, without a preference for, or higher level in, MSNs or cortical projection neurons [4].In the absence of enriched expression of a mutated protein, neuronal subtype vulnerability was assumed to arise from unique protein interactions. For example, in the study of another polyQ disease, spinocerebellar ataxia 7, the interaction between ataxin-7 and the homeobox protein CRX in the retina was reported to specifically lead to pathology [5]. In a followup study, the specific role of CRX was not confirmed [6]. To complicate matters further, the same group recently demonstrated that the interactions between a mutant polyQ protein, Ataxin-1, and 14-3-3epsilon differentially affects disease state in cerebellum and brainstem, both of which are vulnerable regions [7]. The regional distribution of the described huntingtin interacting proteins by and large does not explain MSN vulnerability [8][9][10]. One exception is the htt interacting protein RASD2/Rhes (Ras homologue enriched in striatum), which is striatal-specific. It is a small G-protein that mediates sumoylation of polyQ-htt, and thereby its neurotoxicity.

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Section: Transcriptional Dysregulationmentioning

confidence: 99%

Huntington's Disease and the Striatal Medium Spiny Neuron: Cell-Autonomous and Non-Cell-Autonomous Mechanisms of Disease

Ehrlich

2012

Neurotherapeutics

120

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“…Indirect evidence also supports a beneficial effect of PDE10A inhibition for treatment of HD, as TP-10 treatment increases the probability that medium spiny projection neurons fire in response to cortical input (Threfell et al, 2009) and both genetic ablation of PDE10A and TP-10 treatment result in gene expression changes that are predicted to be neuroprotective in HD (Kleiman et al, 2011). However, PDE10A2 mRNA expression is decreased at the level of transcription by N-mHtt in R6 mouse models of HD (Hu et al, 2004;Gomez et al, 2006). N-mHtt interacts with, and interferes with, the normal function of transcription factors and co-factors required for the appropriate expression of PDE10A2 (Hu et.…”

Section: Discussionmentioning

confidence: 94%

“…The decreased steady state levels of PDE10A2 in the R6 mouse striatum are caused by an altered rate of transcriptional initiation, rather than an alteration in mRNA stability (Hu et al, 2004;Gomez et al, 2006). A comparison of the human and mouse PDE10A2 promoters…”

Section: Expression Of Phosphodiesterase Isoforms Pde1b Pde4a and Pmentioning

confidence: 99%

“…Consequently, PDE1B null mice recapitulate the increased spontaneous locomotor activity and depression observed in HD mouse models and patients. Importantly during HD progression, DARPP-32 mRNA and protein levels www.intechopen.com decrease in an N-mHtt dependent manner (Gomez et al, 2006). This indicates that treatments that alter PDE1B activity may be limited by defects in downstream DARPP-32 levels or activity.…”

Section: Phosphodiesterase 1b Knock-out Causes Hyper-locomotion and Smentioning

confidence: 99%

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Alterations in Expression and Function of Phosphodiesterases in Huntington’s Disease

Laprairie¹,

Hosier²,

Hogel³

et al. 2012

Huntington's Disease - Core Concepts and Current Advances

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“…The precise pathway of toxicity is yet unknown, but evidence suggests that the mutant huntingtin protein interacts with DNA transcription factors, such as CREB (c-AMP response element-binding protein) and dysregulates DNA transcription processes. In particular, there is evidence showing that the mutant huntingtin interferes selectively with transcription factors in the medium spiny neurons (Gomez, et al, 2006). In transgenic mice, Hebb et al (2004) observed decreased levels of PDE10A mRNA before motor symptoms appear and Gomez et al (2006) observed decreased levels of DARPP-32 mRNA in MSNs, but not in other DARPP-32 mRNA expressing tissue, such as the kidneys.…”

Section: The Mutant Huntingtin Protein Destabilizes Cellsmentioning

confidence: 99%

Computational Investigations of Cognitive Impairment in Huntington's Disease

Davelaar¹

2012

Huntington's Disease - Core Concepts and Current Advances

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Brain-specific factors in combination with mutant huntingtin induce gene-specific transcriptional dysregulation

Cited by 14 publications

References 69 publications

Huntington's Disease and the Striatal Medium Spiny Neuron: Cell-Autonomous and Non-Cell-Autonomous Mechanisms of Disease

Huntington's Disease and the Striatal Medium Spiny Neuron: Cell-Autonomous and Non-Cell-Autonomous Mechanisms of Disease

Alterations in Expression and Function of Phosphodiesterases in Huntington’s Disease

Computational Investigations of Cognitive Impairment in Huntington's Disease

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