Decrease in Striatal Enkephalin mRNA in Mouse Models of Huntington’s Disease

Menalled, Liliana; Zanjani, Hadi Shojaeian; MacKenzie, Larami; Koppel, Ahrin; Carpenter, Ellen M.; Zeitlin, Scott; Chesselet, Marie‐Françoise

doi:10.1006/exnr.1999.7327

Cited by 115 publications

(98 citation statements)

References 57 publications

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“…One of the earliest morphological changes in HD is the reduction in enkephalin expression in neurons of the indirect pathway (Menalled et al, 2000;Reiner et al, 1988;Sapp et al, 1995). Our electrophysiological studies in R6/2 mice have demonstrated a transient increase (around 5-7 weeks) of large synaptic events in a subset of MSSNs followed by a progressive reduction of cortical inputs into the striatum (Cepeda et al, 2003).…”

Section: Selective Vulnerability Of Enkephalin-containing Cellsmentioning

confidence: 72%

“…Transgenic animals display overt behavioral symptoms as early as 4-5 weeks of age and die of unknown causes at about 15 weeks. Affected animals display a number of alterations including the formation of neuronal intranuclear inclusions , changes in neurotransmitter receptor expression (Ariano et al, 2002;Cha et al, 1998), and altered signaling mechanisms (Bibb et al, 2000;Luthi-Carter et al, 2000;Menalled et al, 2000). There are also metabolic deficits in transgenic animals (Higgins et al, 1999;Tabrizi et al, 2000).…”

Section: Genetic Mouse Models Of Hdmentioning

confidence: 99%

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The corticostriatal pathway in Huntington's disease

Cepeda

André

et al. 2007

Progress in Neurobiology

279

265

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The corticostriatal pathway provides most of the excitatory glutamatergic input into the striatum and it plays an important role in the development of the phenotype of Huntington's disease (HD). This review summarizes results obtained from genetic HD mouse models concerning various alterations in this pathway. Evidence indicates that dysfunctions of striatal circuits and cortical neurons that make up the corticostriatal pathway occur during the development of the HD phenotype, well before there is significant neuronal cell loss. Morphological changes in the striatum are probably primed initially by alterations in the intrinsic functional properties of striatal medium-sized spiny neurons. Some of these alterations, including increased sensitivity of N-methyl-D-aspartate receptors in subpopulations of neurons, might be constitutively present but ultimately require abnormalities in the corticostriatal inputs for the phenotype to be expressed. Dysfunctions of the corticostriatal pathway are complex and there are multiple changes as demonstrated by significant age-related transient and more chronic interactions with the disease state. There also is growing evidence for changes in cortical microcircuits that interact to induce dysfunctions of the corticostriatal pathway. The conclusions of this review emphasize, first, the general role of neuronal circuits in the expression of the HD phenotype and, second, that both cortical and striatal circuits must be included in attempts to establish a framework for more rational therapeutic strategies in HD. Finally, as changes in cortical and striatal circuitry are complex and in some cases biphasic, therapeutic interventions should be regionally specific and take into account the temporal progression of the phenotype.

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Section: Selective Vulnerability Of Enkephalin-containing Cellsmentioning

confidence: 72%

Section: Genetic Mouse Models Of Hdmentioning

confidence: 99%

The corticostriatal pathway in Huntington's disease

Cepeda

André

et al. 2007

Progress in Neurobiology

279

265

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“…In fact, neuronal loss is rarely seen in any of the knockin mouse models of HD that have been generated (Hickey and Chesselet, 2003;Menalled, 2005). For this reason, the decrease in proenkephalin mRNA seen in the striatum of Hdh Q140/Q140 mice is likely due to a decrease in proenkephalin transcription within HD neurons, rather than the death of HD neurons that express enkephalin (Menalled et al, 2000). In situ hybridization studies performed on brain tissue from patients with presymptomatic Huntington's disease support this idea (Albin et al, 1991).…”

Section: Loss Of P53 Partially Rescues Low Proenkephalin Mrna Levels mentioning

confidence: 99%

“…To test this, we examined the levels of the messenger RNA encoding the neurotransmitter proenkephalin. Analysis has shown that proenkephalin mRNA levels are reduced even in early stage HD patients and presymptomatic carriers (Albin et al, 1991), and this reduction is also seen in many HD animal models (Albin et al, 1991;Menalled et al, 2000). To determine if altering p53 status would rescue the levels of proenkephalin mRNA in our model of HD, we performed northern blot analysis on brain tissue taken from control, p53 −/− , Hdh Q140/Q140 , and Hdh Q140/Q140 p53 −/− mice.…”

Section: Loss Of P53 Partially Rescues Low Proenkephalin Mrna Levels mentioning

confidence: 99%

Genetic interaction between expanded murine Hdh alleles and p53 reveal deleterious effects of p53 on Huntington's disease pathogenesis

Ryan

Zeitlin

Scrable

2006

Neurobiology of Disease

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Huntingtin, the protein product of the Huntington's disease (HD) gene is known to interact with the tumor suppressor p53. It has recently been shown that activation of p53 upregulates the level of huntingtin, both in vitro and in vivo, while p53 deficiency in HD-transgenic flies and mice has been found to be beneficial. To explore further the involvement of p53 in HD pathogenesis, we generated mice homozygous for a mutant allele of Hdh (Hdh Q140 ) and with zero, one, or two functional alleles of p53. p53 deficiency resulted in a reduction of mutant huntingtin expression in brain and testis, an increase in proenkephalin mRNA expression, and a significant increase in nuclear aggregate formation in the striatum. Because aggregation of mutant huntingtin is suggested to be a protective mechanism, both the increase in aggregate load and the restoration of proenkephalin expression suggest a functional rescue of HD phenotypes by p53 deficiency.

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“…These early molecular phenotypes support excitotoxicity, via Ca 2ϩ influx, stemming from decreased mitochondrial ATP synthesis (8) and enhanced NMDA receptor activation (7). They also suggest a role for loss of neuroprotective factors, such as brain-derived neurotrophic factor (12) and proenkephalin (5), caused by reduced levels of cAMP and diminished cAMP signaling via cAMP-dependent protein kinase and CREB-binding protein/cAMP-responsive element-binding protein (CBP/CREB) (8). The dominant phenotypes detected in vivo are also manifest in a genetically precise HD cell model: immortalized STHdh Q111/Q111 striatal neuronal cells, derived from Hdh Q111/Q111 embryos (13).…”

Section: Q111mentioning

confidence: 99%

Enhanced Akt Signaling Is an Early Pro-survival Response That Reflects N-Methyl-D-aspartate Receptor Activation in Huntington's Disease Knock-in Striatal Cells

Ginés

Ivanova

Seong

et al. 2003

Journal of Biological Chemistry

120

110

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Huntington's disease features the loss of striatal neurons that stems from a disease process that is initiated by mutant huntingtin. Early events in the disease cascade, which predate overt pathology in Hdh CAG knock-in mouse striatum, implicate enhanced N-methyl-D-aspartate (NMDA) receptor activation, with excitotoxity caused by aberrant Ca 2؉ influx. Here we demonstrate in precise genetic Huntington's disease mouse and striatal cell models that these early phenotypes are associated with activation of the Akt pro-survival signaling pathway. Elevated levels of activated Ser (

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Decrease in Striatal Enkephalin mRNA in Mouse Models of Huntington’s Disease

Cited by 115 publications

References 57 publications

The corticostriatal pathway in Huntington's disease

The corticostriatal pathway in Huntington's disease

Genetic interaction between expanded murine Hdh alleles and p53 reveal deleterious effects of p53 on Huntington's disease pathogenesis

Enhanced Akt Signaling Is an Early Pro-survival Response That Reflects N-Methyl-D-aspartate Receptor Activation in Huntington's Disease Knock-in Striatal Cells

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