Abstract

Huntington disease is caused by a polyglutamine expansion in the huntingtin protein (Htt) and is associated with excitotoxic death of striatal neurons. Group I metabotropic glutamate receptors (mGluRs) that are coupled to inositol 1,4,5-triphosphate formation and the release of intracellular Ca(2+) stores play an important role in regulating neuronal function. We show here that mGluRs interact with the Htt-binding protein optineurin that is also linked to normal pressure open angled glaucoma and, when expressed in HEK 293 cells, optineurin functions to antagonize agonist-stimulated mGluR1a signaling. We find that Htt is co-precipitated with mGluR1a and that mutant Htt functions to facilitate optineurin-mediated attenuation of mGluR1a signaling. In striatal cell lines derived from Htt(Q111/Q111) mutant knock-in mice mGluR5-stimulated inositol phosphate formation is also severely impaired when compared with striatal cells derived from Htt(Q7/Q7) knock-in mice. In addition, we show that a missense single nucleotide polymorphism optineurin H486R variant previously identified to be associated with glaucoma is selectively impaired in mutant Htt binding. Although optineurin H486R retains the capacity to bind to mGluR1a, optineurin H486R-dependent attenuation of mGluR1a signaling is not enhanced by the expression of mutant Htt. Because G protein-coupled receptor kinase 2 (GRK2) protein expression is relatively low in striatal tissue, we propose that optineurin may substitute for GRK2 in the striatum to mediate mGluR desensitization. Taken together, these studies identify a novel mechanism for mGluR desensitization and an additional biochemical link between altered glutamate receptor signaling and Huntington disease.

Highlights

  • Unstable CAG repeat resulting in a polyglutamine expansion in the amino-terminal region of the huntingtin (Htt) protein, a ubiquitously expressed and evolutionary conserved protein [1]

  • To verify the specificity of the yeast two-hybrid interaction, we show that HA-tagged OPTN can be coprecipitated with an mGluR1a but not an angiotensin II type 1A receptor, carboxyl-terminal tails (C-tails) glutathione S-transferase (GST) fusion protein (Fig. 1B) and can be co-immunoprecipitated from HEK 293 cells with either FLAG-tagged mGluR1a or mGluR5a (Fig. 1C)

  • We provide evidence that OPTN can substitute for G protein-coupled receptor kinase 2 (GRK2) to mediate the attenuation of metabotropic glutamate receptors (mGluRs) signaling

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Summary

Introduction

Unstable CAG repeat resulting in a polyglutamine expansion in the amino-terminal region of the huntingtin (Htt) protein, a ubiquitously expressed and evolutionary conserved protein [1]. Unlike what is observed for GRK2, OPTN expression in HEK 293 cells leads to increased basal mGluR1a activity (Fig. 2B).

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