UMMS Affiliation

Program in Gene Function and Expression; Program in Molecular Medicine

Publication Date

2012-09-05

Document Type

Article

Subjects

Nerve Tissue Proteins; Neurons; Nerve Degeneration; beta Catenin; Sirtuin 1; Forkhead Transcription Factors

Disciplines

Genetics and Genomics | Neuroscience and Neurobiology

Abstract

One of the current challenges of neurodegenerative disease research is to determine whether signaling pathways that are essential to cellular homeostasis might contribute to neuronal survival and modulate the pathogenic process in human disease. In Caenorhabditis elegans, sir-2.1/SIRT1 overexpression protects neurons from the early phases of expanded polyglutamine (polyQ) toxicity, and this protection requires the longevity-promoting factor daf-16/FOXO. Here, we show that this neuroprotective effect also requires the DAF-16/FOXO partner bar-1/beta-catenin and putative DAF-16-regulated gene ucp-4, the sole mitochondrial uncoupling protein (UCP) in nematodes. These results fit with a previously proposed mechanism in which the beta-catenin FOXO and SIRT1 proteins may together regulate gene expression and cell survival. Knockdown of beta-catenin enhanced the vulnerability to cell death of mutant-huntingtin striatal cells derived from the HdhQ111 knock-in mice. In addition, this effect was compensated by SIRT1 overexpression and accompanied by the modulation of neuronal UCP expression levels, further highlighting a cross-talk between beta-catenin and SIRT1 in the modulation of mutant polyQ cytoxicity. Taken together, these results suggest that integration of beta-catenin, sirtuin and FOXO signaling protects from the early phases of mutant huntingtin toxicity.

Rights and Permissions

This article is freely available online through the Journal of Neuroscience Open Choice option.

DOI of Published Version

10.1523/JNEUROSCI.0277-12.2012

Source

J Neurosci. 2012 Sep 5;32(36):12630-40. Link to article on publisher's site

Journal/Book/Conference Title

The Journal of neuroscience : the official journal of the Society for Neuroscience

Related Resources

Link to Article in PubMed

PubMed ID

22956852

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