Oral uridine pro-drug PN401 is neuroprotective in the R6/2 and N171-82Q mouse models of Huntington's disease

Saydoff, Joel A.; Garcia, Rolando A.G.; Browne, Susan; Liu, Liansheng; Sheng, Jin; Brenneman, D.E.; Hu, Zhiwei; Cardin, Sylvain; González, Aldo; Borstel, Reid W. von; Gregorio, Jason; Burr, Holly; Beal, M. Flint

doi:10.1016/j.nbd.2006.08.011

Cited by 26 publications

(21 citation statements)

References 56 publications

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“…[46][47][48] Although several other interesting studies have demonstrated potential neuroprotective properties of different factors investigated in the context of HD, none of these factors have afforded the same dramatic protection against excitotoxicity as is in the transgenic HD mouse models we have described in this review article (see e.g. Saydoff et al, 49 Dedeoglu et al, 50 McBride et al, 51 Jin et al 52 and Ferrante et al 53 ).…”

Section: Possible Mechanisms Involved In Huntingtin-mediated Resistancementioning

confidence: 86%

Mutant huntingtin can paradoxically protect neurons from death

Züchner

Brundin

2007

Cell Death Differ

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Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a mutation in the gene huntingtin and characterized by motor, cognitive and psychiatric symptoms. Huntingtin contains a CAG repeat in exon 1. An expansion of this CAG repeat above 35 results in misfolding of Huntingtin, giving rise to protein aggregates and neuronal cell death. There are several transgenic HD mouse models that reproduce most of the features of the human disorder, for example protein inclusions, some neurodegeneration as well as motor and cognitive symptoms. At the same time, a subgroup of the HD transgenic mouse models exhibit dramatically reduced susceptibility to excitotoxicity. The mechanism behind this is unknown. Here, we review the literature regarding this phenomenon, attempt to explain what protein domains are crucial for this phenomenon and point toward a putative mechanism. We suggest, that the C-terminal domain of exon 1 Huntingtin, namely the proline rich domain, is responsible for mediating a neuroprotective effect against excitotoxicity. Furthermore, we point out the possible importance of this mechanism for future therapies in neurological disorders that have been suggested to be associated with excitotoxicity, for example Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis.

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Section: Possible Mechanisms Involved In Huntingtin-mediated Resistancementioning

confidence: 86%

Mutant huntingtin can paradoxically protect neurons from death

Züchner

Brundin

2007

Cell Death Differ

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“…Compared to the R6/2 mice, the N171-82Q model of HD has a longer N-terminal fragment of huntingtin and shows a relatively delayed onset of disease symptoms (Beal and Ferrante, 2004). Histology-based studies in this model have reported neuronal degeneration in the cortex, striatum, amygdala, hippocampus and piriform cortex (Saydoff et al, 2006). Significant progressive atrophy in these brain regions was detected in N171-82Q mice in the present study (Figure 3).…”

Section: Discussionmentioning

confidence: 97%

Spatiotemporal mapping of brain atrophy in mouse models of Huntington's disease using longitudinal in vivo magnetic resonance imaging

Duan¹,

Hou²,

Rakesh³

et al. 2012

NeuroImage

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Mouse models of Huntington's disease (HD), that recapitulate some of the phenotypic features of human HD, play a crucial role in investigating disease mechanisms and testing potential therapeutic approaches. Longitudinal studies of these models can yield valuable insights into the temporal course of disease progression and the effect of drug treatments on the progressive phenotypes. Atrophy of the brain, particularly the striatum, is a characteristic phenotype of human HD, is known to begin long before the onset of motor symptoms, and correlates strongly with clinical features. Elucidating the spatial and temporal patterns of atrophy in HD mouse models is important to characterize the phenotypes of these models, as well as evaluate the effects of neuroprotective treatments at specific time frames during disease progression. In this study, three dimensional in vivo magnetic resonance imaging (MRI) and automated longitudinal deformation-based morphological analysis was used to elucidate the spatial and temporal patterns of brain atrophy in the R6/2 and N171-82Q mouse models of HD. Using an established MRI-based brain atlas and mixed-effects modeling of deformation-based metrics, we report the rates of progression and region-specificity of brain atrophy in the two models. Further, the longitudinal analysis approach was used to evaluate the effects of sertraline and coenzyme Q10 (CoQ10) treatments on progressive atrophy in the N171-82Q model. Sertraline treatment resulted in significant slowing of atrophy, especially in the striatum and frontal cortex regions, while no significant effects of CoQ10 treatment were observed. Progressive cortical and striatal atrophy in the N171-82Q mice showed significant positive correlations with measured functional deficits. The findings of this report can be used for future testing and comparison of potential therapeutics in mouse models of HD.

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“…In agreement with these observations, low BDNF expression has been observed in various brain regions of HD patients, including frontal cortex, striatum, hippocampus, substantia nigra, and cerebellum (Zuccato et al, 2001; Seo et al, 2004). In most mouse models of HD, the abundance of BDNF protein (Duan et al, 2003, 2008; Saydoff et al, 2006; Simmons et al, 2009; Xie et al, 2010) and Bdnf mRNA is decreased in mutant compared to normal mice in cortex, striatum and hippocampus (Zuccato et al, 2005; Pang et al, 2006; Zajac et al, 2010). It should be noted that striatal neurons express very low amount of BDNF mRNA (Altar et al, 1997).…”

Section: Htt Bdnf and Mood Disordersmentioning

confidence: 99%

Mood disorders in Huntington's disease: from behavior to cellular and molecular mechanisms

Pla

Orvoën

Saudou

et al. 2014

Front. Behav. Neurosci.

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Huntington's disease (HD) is a neurodegenerative disorder that is best known for its effect on motor control. Mood disturbances such as depression, anxiety, and irritability also have a high prevalence in patients with HD, and often start before the onset of motor symptoms. Various rodent models of HD recapitulate the anxiety/depressive behavior seen in patients. HD is caused by an expanded polyglutamine stretch in the N-terminal part of a 350 kDa protein called huntingtin (HTT). HTT is ubiquitously expressed and is implicated in several cellular functions including control of transcription, vesicular trafficking, ciliogenesis, and mitosis. This review summarizes progress in efforts to understand the cellular and molecular mechanisms underlying behavioral disorders in patients with HD. Dysfunctional HTT affects cellular pathways that are involved in mood disorders or in the response to antidepressants, including BDNF/TrkB and serotonergic signaling. Moreover, HTT affects adult hippocampal neurogenesis, a physiological phenomenon that is implicated in some of the behavioral effects of antidepressants and is linked to the control of anxiety. These findings are consistent with the emerging role of wild-type HTT as a crucial component of neuronal development and physiology. Thus, the pathogenic polyQ expansion in HTT could lead to mood disorders not only by the gain of a new toxic function but also by the perturbation of its normal function.

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Oral uridine pro-drug PN401 is neuroprotective in the R6/2 and N171-82Q mouse models of Huntington's disease

Cited by 26 publications

References 56 publications

Mutant huntingtin can paradoxically protect neurons from death

Mutant huntingtin can paradoxically protect neurons from death

Spatiotemporal mapping of brain atrophy in mouse models of Huntington's disease using longitudinal in vivo magnetic resonance imaging

Mood disorders in Huntington's disease: from behavior to cellular and molecular mechanisms

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