Dataset Information

Phosphodiesterase 10A inhibition improves cortico-basal ganglia function in Huntington’s disease models

ABSTRACT: Using Huntington’s disease (HD) mouse models that quantitatively replicate the reduction of striatal Phoshodiesterase 10 (PDE10) levels in manifest Huntington’s disease patients, we demonstrate the potential therapeutic benefit of PDE10 inhibition on correcting basal ganglia circuitry deficits thought to drive disease symptomology in patients. PDE10 inhibition acutely restored corticostriatal input and boosted cortically driven indirect pathway activity in HD models with compromised PDE10 levels. We show that cyclic nucleotide signaling processes are impaired in the models, and that elevation of both the cAMP and cGMP nucleotides afforded by PDE10 inhibition are required for this rescue. Global phosphoproteomic profiling of striatal proteins in response to PDE10 inhibition provide novel information on the plausible neural substrates responsible for the improvement. Finally, we show that long-term chronic treatment of the Q175 knock-in mouse model with PDE10A inhibitors, starting at a presymptomatic age, showed improvements, above and beyond those seen during acute administration, including a partial reversal of striatal deregulated transcripts predominantly driven through activation of the AP-1 and CREB transcription factor complexes, and a prevention of the emergence of some cardinal HD neurophysiological deficits.

OTHER RELATED OMICS DATASETS IN: PRJNA352400

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Striatum, Brain

DISEASE(S): Huntington Disease

SUBMITTER: Manuela Machatti

LAB HEAD: Christoph Schaab

PROVIDER: PXD005138 | Pride | 2016-12-02

REPOSITORIES: Pride

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Publications

Phosphodiesterase 10A Inhibition Improves Cortico-Basal Ganglia Function in Huntington's Disease Models.

Beaumont Vahri V Zhong Sheng S Lin Hai H Xu WenJin W Bradaia Amyaouch A Steidl Esther E Gleyzes Melanie M Wadel Kristian K Buisson Bruno B Padovan-Neto Fernando E FE Chakroborty Shreaya S Ward Karen M KM Harms John F JF Beltran Jose J Kwan Mei M Ghavami Afshin A Häggkvist Jenny J Tóth Miklós M Halldin Christer C Varrone Andrea A Schaab Christoph C Dybowski J Nikolaj JN Elschenbroich Sarah S Lehtimäki Kimmo K Heikkinen Taneli T Park Larry L Rosinski James J Mrzljak Ladislav L Lavery Daniel D West Anthony R AR Schmidt Christopher J CJ Zaleska Margaret M MM Munoz-Sanjuan Ignacio I

Neuron 20161201 6

Huntington's disease (HD) symptoms are driven to a large extent by dysfunction of the basal ganglia circuitry. HD patients exhibit reduced striatal phoshodiesterase 10 (PDE10) levels. Using HD mouse models that exhibit reduced PDE10, we demonstrate the benefit of pharmacologic PDE10 inhibition to acutely correct basal ganglia circuitry deficits. PDE10 inhibition restored corticostriatal input and boosted cortically driven indirect pathway activity. Cyclic nucleotide signaling is impaired in HD m ...[more]

PMID: 27916455

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Project description:Increasing evidence has demonstrated that epigenetic factors can profoundly influence gene expression and, in turn, influence resistance or susceptibility to disease. Epigenetic drugs, such as histone deacetylase (HDAC) inhibitors, are finding their way into clinical practice, although their exact mechanisms of action are unclear. To identify mechanisms associated with HDAC inhibition, we performed microarray analysis on brain and muscle samples treated with the HDAC1/3-targeting inhibitor, HDACi 4b. Pathways analyses of microarray datasets implicate DNA methylation as significantly associated with HDAC inhibition. Further assessment of DNA methylation changes elicited by HDACi 4b in human fibroblasts from normal controls and patients with Huntington's disease (HD) using the Infinium HumanMethylation450 BeadChip revealed a limited, but overlapping, subset of methylated CpG sites that were altered by HDAC inhibition in both normal and HD cells. Among the altered loci of Y chromosome-linked genes, KDM5D, which encodes Lys (K)-specific demethylase 5D, showed increased methylation at several CpG sites in both normal and HD cells, as well as in DNA isolated from sperm from drug-treated male mice. Further, we demonstrate that first filial generation (F1) offspring from drug-treated male HD transgenic mice show significantly improved HD disease phenotypes compared with F1 offspring from vehicle-treated male HD transgenic mice, in association with increased Kdm5d expression, and decreased histone H3 Lys4 (K4) (H3K4) methylation in the CNS of male offspring. Additionally, we show that overexpression of Kdm5d in mutant HD striatal cells significantly improves metabolic deficits. These findings indicate that HDAC inhibitors can elicit transgenerational effects, via cross-talk between different epigenetic mechanisms, to have an impact on disease phenotypes in a beneficial manner. Bisulphite converted DNA from the 12 samples were hybridised to the Illumina Infinium 27k Human Methylation Beadchip v1.2. We demonstrate that histone deacetylase (HDAC) inhibition can elicit changes in DNA methylation in Huntington’s disease (HD) human fibroblasts, as well as in sperm from HD transgenic mice, in association with DNA methylation-related gene expression changes. We suggest that alterations in sperm DNA methylation lead to transgenerational effects, and, accordingly, we show that first filial generation (F1) offspring of HDAC inhibitor-treated male HD transgenic mice show improved HD disease phenotypes compared with F1 offspring from vehicle-treated male HD transgenic mice. These findings have significant implications for human health because they enforce the concept that ancestral drug exposure may be a major molecular factor that can affect disease phenotypes, yet in a positive manner. Further, we implicate Lys (K)-specific demethylase 5d expression in this phenomenon.

Dataset Information

Phosphodiesterase 10A inhibition improves cortico-basal ganglia function in Huntington’s disease models

Publications

Phosphodiesterase 10A Inhibition Improves Cortico-Basal Ganglia Function in Huntington's Disease Models.

Similar Datasets

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