Dataset Information

Decreased striatal RGS2 expression is neuroprotective in Huntington's disease (HD) and exemplifies a compensatory aspect of HD-induced gene regulation.

ABSTRACT:

Background

The molecular phenotype of Huntington's disease (HD) is known to comprise highly reproducible changes in gene expression involving striatal signaling genes. Here we test whether individual changes in striatal gene expression are capable of mitigating HD-related neurotoxicity.

Methodology/principal findings

We used protein-encoding and shRNA-expressing lentiviral vectors to evaluate the effects of RGS2, RASD2, STEP and NNAT downregulation in HD. Of these four genes, only RGS2 and RASD2 modified mutant htt fragment toxicity in cultured rat primary striatal neurons. In both cases, disease modulation was in the opposite of the predicted direction: whereas decreased expression of RGS2 and RASD2 was associated with the HD condition, restoring expression enhanced degeneration of striatal cells. Conversely, silencing of RGS2 or RASD2 enhanced disease-related changes in gene expression and resulted in significant neuroprotection. These results indicate that RGS2 and RASD2 downregulation comprises a compensatory response that allows neurons to better tolerate huntingtin toxicity. Assessment of the possible mechanism of RGS2-mediated neuroprotection showed that RGS2 downregulation enhanced ERK activation. These results establish a novel link between the inhibition of RGS2 and neuroprotective modulation of ERK activity.

Conclusions

Our findings both identify RGS2 downregulation as a novel compensatory response in HD neurons and suggest that RGS2 inhibition might be considered as an innovative target for neuroprotective drug development.

SUBMITTER: Seredenina T

PROVIDER: S-EPMC3136499 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Publications

Decreased striatal RGS2 expression is neuroprotective in Huntington's disease (HD) and exemplifies a compensatory aspect of HD-induced gene regulation.

Seredenina Tamara T Gokce Ozgun O Luthi-Carter Ruth R

PloS one 20110714 7

<h4>Background</h4>The molecular phenotype of Huntington's disease (HD) is known to comprise highly reproducible changes in gene expression involving striatal signaling genes. Here we test whether individual changes in striatal gene expression are capable of mitigating HD-related neurotoxicity.<h4>Methodology/principal findings</h4>We used protein-encoding and shRNA-expressing lentiviral vectors to evaluate the effects of RGS2, RASD2, STEP and NNAT downregulation in HD. Of these four genes, only ...[more]

PMID: 21779398

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Project description:BackgroundHuntington's disease (HD) causes progressive atrophy to the striatum, a critical node in frontostriatal circuitry. Maintenance of motor function is dependent on functional connectivity of these premotor, motor, and dorsolateral frontostriatal circuits, and structural integrity of the striatum itself. We aimed to investigate whether size and shape of the striatum as a measure of frontostriatal circuit structural integrity was correlated with functional frontostriatal electrophysiological neural premotor processing (contingent negative variation, CNV), to better understand motoric structure-function relationships in early HD.MethodsMagnetic resonance imaging (MRI) scans and electrophysiological (EEG) measures of premotor processing were obtained from a combined HD group (12 presymptomatic, 7 symptomatic). Manual segmentation of caudate and putamen was conducted with subsequent shape analysis. Separate correlational analyses (volume and shape) included covariates of age, gender, intracranial volume, and time between EEG and MRI.ResultsRight caudate volume correlated with early CNV latency over frontocentral regions and late CNV frontally, whereas right caudate shape correlated with early CNV latency centrally. Left caudate volume correlated with early CNV latency over centroparietal regions and late CNV frontally. Right and left putamen volumes correlated with early CNV latency frontally, and right and left putamen shape/volume correlated with parietal CNV slope.ConclusionsTiming (latency) and pattern (slope) of frontostriatal circuit-mediated premotor functional activation across scalp regions were correlated with abnormalities in structural integrity of the key frontostriatal circuit component, the striatum (size and shape). This was accompanied by normal reaction times, suggesting it may be undetected in regular tasks due to preserved motor "performance." Such differences in functional activation may reflect atrophy-based frontostriatal circuitry despecialization and/or compensatory recruitment of additional brain regions.

Dataset Information

Decreased striatal RGS2 expression is neuroprotective in Huntington's disease (HD) and exemplifies a compensatory aspect of HD-induced gene regulation.

Background

Methodology/principal findings

Conclusions

Publications

Decreased striatal RGS2 expression is neuroprotective in Huntington's disease (HD) and exemplifies a compensatory aspect of HD-induced gene regulation.

Similar Datasets

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