In vivo evidence of cerebellar atrophy and cerebral white matter loss in Huntington disease

Fennema-Notestine, Christine; Archibald, Sarah; Jacobson, Mark W.; Corey–Bloom, Jody; Paulsen, Jane S.; Peavy, Guerry M.; Gamst, Anthony; Hamilton, James; Salmon, David P.; Jernigan, Terry L.

doi:10.1212/01.wnl.0000138434.68093.67

Cited by 141 publications

(114 citation statements)

References 33 publications

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“…From the microarray data, the cerebellum showed the most robust treatment effect, which is interesting in light of studies suggesting that the cerebellum may play a more significant role in the symptomatology of HD than previously thought (28). Expression deficits for aquaporin 1 (Aqp1), claudin 1 (Cldn1), calmodulin-like 4 (Calml4), folate receptor 1 (Folr1), chloride intracellular channel 6 (Clic6), and ectonucleotide pyrophosphatase/phosphodiesterase 2 (Enpp2), detected in the cerebellum of 5-month-old R6/2 300Q transgenic mice compared with age-matched WT mice, were almost completely reversed by HDACi 4b treatment (Fig.…”

Section: Hdaci 4b Treatment Ameliorates Gene Expression Abnormalities Inmentioning

confidence: 63%

The HDAC inhibitor 4b ameliorates the disease phenotype and transcriptional abnormalities in Huntington's disease transgenic mice

Thomas

Coppola²,

Desplats³

et al. 2008

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

270

257

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Transcriptional dysregulation has emerged as a core pathologic feature of Huntington's disease (HD), one of several triplet-repeat disorders characterized by movement deficits and cognitive dysfunction. Although the mechanisms contributing to the gene expression deficits remain unknown, therapeutic strategies have aimed to improve transcriptional output via modulation of chromatin structure. Recent studies have demonstrated therapeutic effects of commercially available histone deacetylase (HDAC) inhibitors in several HD models; however, the therapeutic value of these compounds is limited by their toxic effects. Here, beneficial effects of a novel pimelic diphenylamide HDAC inhibitor, HDACi 4b, in an HD mouse model are reported. Chronic oral administration of HDACi 4b, beginning after the onset of motor deficits, significantly improved motor performance, overall appearance, and body weight of symptomatic R6/2 300Q transgenic mice. These effects were associated with significant attenuation of gross brain-size decline and striatal atrophy. Microarray studies revealed that HDACi 4b treatment ameliorated, in part, alterations in gene expression caused by the presence of mutant huntingtin protein in the striatum, cortex, and cerebellum of R6/2 300Q transgenic mice. For selected genes, HDACi 4b treatment reversed histone H3 hypoacetylation observed in the presence of mutant huntingtin, in association with correction of mRNA expression levels. These findings suggest that HDACi 4b, and possibly related HDAC inhibitors, may offer clinical benefit for HD patients and provide a novel set of potential biomarkers for clinical assessment.rologic disorder caused by a CAG repeat expansion within the coding region of the HD gene (Htt), resulting in a mutant protein (htt) with a lengthened polyglutamine tract (1). Mutant htt protein has been shown to disrupt transcription by multiple mechanisms, but it is unclear which are most important to pathology (2-4). By interacting with specific transcription factors, htt can alter the expression of clusters of genes controlled by those factors. For example, several genes driven by Sp1, which has been shown to interact with htt (5, 6), show decreased mRNA expression in human HD and in mouse models of HD (7). Alternatively, htt may have more global effects on transcription by disrupting core transcriptional machinery (8, 9) or by altering posttranslational modifications of histones, resulting in condensed chromatin structure (10-13). Understanding the basis for transcriptional dysregulation is important for choosing appropriate drug-discovery strategies.Manifestations of transcriptional dysregulation are evident from several gene-profiling studies, which have revealed alterations in the expression of large numbers of genes in the brains of different HD mouse models and in human subjects with HD (7, 14-16). Many of the expression changes in mouse models are observed in early stages of illness before the onset of symptoms, suggesting that gene expression alterations may be pathogenic.Because o...

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Section: Hdaci 4b Treatment Ameliorates Gene Expression Abnormalities Inmentioning

confidence: 63%

The HDAC inhibitor 4b ameliorates the disease phenotype and transcriptional abnormalities in Huntington's disease transgenic mice

Thomas

Coppola²,

Desplats³

et al. 2008

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

270

257

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“…Cerebellar inclusions are not typically found in the brains of adult-onset HD patients. However, cerebellar pathology has been reported in juvenile-onset HD cases, which are the most severe forms of the disease, and interestingly, in Hdh140 knock-in mice as early as 4 months of age (14,(27)(28)(29)(30). The abundant inclusions in HD-N171-82Q cerebellar neurons provide a second target for assessing the effects of AAV.shHD2.1 on target protein levels.…”

Section: Aavshhd21 Reduces Hd-n171-82q Expression In Vivomentioning

confidence: 99%

RNA interference improves motor and neuropathological abnormalities in a Huntington's disease mouse model

Harper

Staber

et al. 2005

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

607

474

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Huntington's disease (HD) is a fatal, dominant neurogenetic disorder. HD results from polyglutamine repeat expansion (CAG codon, Q) in exon 1 of HD, conferring a toxic gain of function on the protein huntingtin (htt). Currently, no preventative treatment exists for HD. RNA interference (RNAi) has emerged as a potential therapeutic tool for treating dominant diseases by directly reducing disease gene expression. Here, we show that RNAi directed against mutant human htt reduced htt mRNA and protein expression in cell culture and in HD mouse brain. Importantly, htt gene silencing improved behavioral and neuropathological abnormalities associated with HD. Our data provide support for the further development of RNAi for HD therapy.short hairpin RNAs ͉ triplet repeat diseases ͉ gene therapy ͉ nanomedicine

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“…1 In patients, progressive widespread brain atrophy, 2,3 leading to severe motor disability over time, is associated with early peripheral tissue dysfunction such as loss of body weight. 4,5 Hence, the pathological involvement of non-nervous tissues may contribute to the clinical features of HD.…”

Section: Introductionmentioning

confidence: 99%

Increased apoptosis, huntingtin inclusions and altered differentiation in muscle cell cultures from Huntington's disease subjects

et al. 2006

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Mutated huntingtin (htt) is ubiquitously expressed in tissues of Huntington's disease (HD) patients. In the brain, the mutated protein leads to neuronal cell dysfunction and death, associated with formation of htt-positive inclusions. Given increasing evidence of abnormalities in HD skeletal muscle, we extensively analyzed primary muscle cell cultures from seven HD subjects (including two unaffected mutation carriers). Myoblasts from presymptomatic and symptomatic HD subjects showed cellular abnormalities in vitro, namely mitochondrial depolarization, cytochrome c release, increased caspase-3, -8, and -9 activities, and defective cell differentiation. Another notable feature was the formation of htt inclusions in differentiated myotubes. This study helps to advance current knowledge about the downstream effects of the htt mutation in human tissues. Further applications may include drug screening using this human cellular model.

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In vivo evidence of cerebellar atrophy and cerebral white matter loss in Huntington disease

Abstract: The cerebellum and the integrity of cerebral white matter may play a more significant role in the symptomatology of HD than previously thought. Furthermore, changes in cortical gray and cerebral white matter were related to caudate atrophy, supporting a similar mechanism of degeneration.

Cited by 141 publications

References 33 publications

The HDAC inhibitor 4b ameliorates the disease phenotype and transcriptional abnormalities in Huntington's disease transgenic mice

The HDAC inhibitor 4b ameliorates the disease phenotype and transcriptional abnormalities in Huntington's disease transgenic mice

RNA interference improves motor and neuropathological abnormalities in a Huntington's disease mouse model

Increased apoptosis, huntingtin inclusions and altered differentiation in muscle cell cultures from Huntington's disease subjects

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