Specific progressive cAMP reduction implicates energy deficit in presymptomatic Huntington's disease knock-in mice

Ginés, Sílvia; Seong, Ihn Sik; Fossale, Elisa; Ivanova, Elena; Trettel, Flavia; Gusella, James F.; Wheeler, Vanessa C.; Persichetti, Francesca; MacDonald, Marcy E.

doi:10.1093/hmg/ddg046

Cited by 253 publications

(136 citation statements)

References 40 publications

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“…These data confirm that HD mouse models replicate the human pattern of neuronal disease. Relative to MSNs from nontransgenic or YAC18 mice, isolated MSNs from "knock-in" and YAC128 polyQ-htt mice demonstrate mitochondrial dysfunction, enhanced N-methyl-D-aspartate (NMDA) receptor signaling, and increased sensitivity to excitotoxicity [34][35][36][37]. A caveat, however, is that it is unknown whether these isolated neurons have already been compromised in vivo.…”

Section: Evidence Supporting Intrinsic Vulnerability Of Msns In Hdmentioning

confidence: 99%

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

Ehrlich

2012

Neurotherapeutics

126

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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: Evidence Supporting Intrinsic Vulnerability Of Msns In Hdmentioning

confidence: 99%

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

Ehrlich

2012

Neurotherapeutics

126

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“…20 This cell model of HD has been extensively used for identifying molecular alterations in HD. [41][42][43][44][45][46][47][48] Cell culture and transfection. (Cat No.…”

Section: O N O T D I S T R I B U T Ementioning

confidence: 99%

Micro RNA -214,-150,-146a and-125b targetHuntingtingene

Sinha¹,

Ghose²,

Bhattarcharyya³

2011

RNA Biology

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“…3A). The metabolic activity of Q111 cells is only half that of Q7 cells (23). Overexpressing IPMK alleviates this abnormality (Fig.…”

Section: Ipmk Expression Rescues Mhtt-induced Deficits In Mitochondrialmentioning

confidence: 89%

Huntington’s disease: Neural dysfunction linked to inositol polyphosphate multikinase

Ahmed

Sbodio

Harraz

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Huntington's disease (HD) is a progressive neurodegenerative disease caused by a glutamine repeat expansion in mutant huntingtin (mHtt). Despite the known genetic cause of HD, the pathophysiology of this disease remains to be elucidated. Inositol polyphosphate multikinase (IPMK) is an enzyme that displays soluble inositol phosphate kinase activity, lipid kinase activity, and various noncatalytic interactions. We report a severe loss of IPMK in the striatum of HD patients and in several cellular and animal models of the disease. This depletion reflects mHtt-induced impairment of COUP-TF-interacting protein 2 (Ctip2), a striatal-enriched transcription factor for IPMK, as well as alterations in IPMK protein stability. IPMK overexpression reverses the metabolic activity deficit in a cell model of HD. IPMK depletion appears to mediate neural dysfunction, because intrastriatal delivery of IPMK abates the progression of motor abnormalities and rescues striatal pathology in transgenic murine models of HD.Huntington's disease | inositol polyphosphate multikinase | IPMK | Ctip2 | Akt

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Specific progressive cAMP reduction implicates energy deficit in presymptomatic Huntington's disease knock-in mice

Cited by 253 publications

References 40 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

Micro RNA -214,-150,-146a and-125b targetHuntingtingene

Huntington’s disease: Neural dysfunction linked to inositol polyphosphate multikinase

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