Inhibition of Metabotropic Glutamate Receptor Signaling by the Huntingtin-binding Protein Optineurin

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 Ca2+ 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 HttQ111/Q111 mutant knock-in mice mGluR5-stimulated inositol phosphate formation is also severely impaired when compared with striatal cells derived from HttQ7/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. 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 Ca2+ 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 HttQ111/Q111 mutant knock-in mice mGluR5-stimulated inositol phosphate formation is also severely impaired when compared with striatal cells derived from HttQ7/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. Huntington disease (HD) 4The abbreviations used are: HD, Huntington disease; GPCR, G protein-coupled receptor; GRK, G protein-coupled receptor kinase; Htt, huntingtin; IP3, inositol 1,4,5-triphosphate; mGluR, metabotropic glutamate receptor; OPTN, optineurin; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; NMDA, N-methyl-d-aspartate; HA, hemagglutinin; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; GST, glutathione S-transferase; HBSS, HEPES-buffered saline solution; PBS, phosphate-buffered saline; C-tail, carboxyl-terminal tail; N-Htt, amino-terminal domain of Htt. is an autosomal-dominant neurodegenerative disorder manifested by symptoms of involuntary body movement, loss of cognitive function, and psychiatric disturbance, which inevitably leads to death (1Cell. 1993; 72: 971-983Abstract Full Text PDF PubMed Scopus (7281) Google Scholar, 2Li S.H. Li X.J. Trends Genet. 2004; 20: 146-154Abstract Full Text Full Text PDF PubMed Scopus (449) Google Scholar, 3Young A.B. J. Clin. Investig. 2003; 111: 299-302Crossref PubMed Scopus (92) Google Scholar, 4Harjes P. Wanker E.E. Trends Biochem. Sci. 2003; 28: 425-433Abstract Full Text Full Text PDF PubMed Scopus (433) Google Scholar). The HD gene mutation consists of an 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 (1Cell. 1993; 72: 971-983Abstract Full Text PDF PubMed Scopus (7281) Google Scholar). It is the polyglutamine expansion of the Htt amino terminus that is proposed to cause progressive widespread neuronal death in the neocortex and the striatum of HD patients. Although the precise function of Htt in cells is not completely understood, analysis of the proteins with which Htt interacts suggests that Htt plays a role in regulating clathrin-coated vesicle-mediated endocytosis, neuronal survival, vesicle transport, morphogenesis, calcium homeostasis, and transcriptional regulation (4Harjes P. Wanker E.E. Trends Biochem. Sci. 2003; 28: 425-433Abstract Full Text Full Text PDF PubMed Scopus (433) Google Scholar). Glutamate-mediated neurotoxicity has been postulated to play an important role in the pathogenesis and excitotoxic neuronal cell loss in HD (5DiFiglia M. Trends Neurosci. 1990; 13: 286-289Abstract Full Text PDF PubMed Scopus (421) Google Scholar, 6Beal M.F. Ferrante R.J. Swartz K.J. Kowall N.W. J. Neurosci. 1991; 11: 1649-1659Crossref PubMed Google Scholar, 7Storey E. Kowall N.W. Finn S.F. Mazurek M.F. Beal M.F. Ann. Neurol. 1992; 32: 526-534Crossref PubMed Scopus (55) Google Scholar, 8Nicoletti F. Bruno V. Copani A. Casabona G. Knopfel T. Trends Neurosci. 1996; 19: 267-271Abstract Full Text Full Text PDF PubMed Scopus (406) Google Scholar, 9Calabresi P. Centonze D. Pisani A. Bernardi G. Exp. Neurol. 1999; 158: 97-108Crossref PubMed Scopus (98) Google Scholar). The receptors for glutamate are classified into two types: ionotropic and metabotropic (10Conn P.J. Pin J.-P. Annu. Rev. Pharmacol. Toxicol. 1997; 37: 205-237Crossref PubMed Scopus (2748) Google Scholar). The ionotropic receptors comprise cation-specific ion channels that mediate fast excitatory glutamate responses and are subdivided into AMPA/kainate and NMDA receptors. There is a considerable body of evidence to support the idea that glutamate released from cortical afferents may regulate the excitotoxic damage observed in HD by activating both NMDA and AMPA/kainate receptors (5DiFiglia M. Trends Neurosci. 1990; 13: 286-289Abstract Full Text PDF PubMed Scopus (421) Google Scholar, 6Beal M.F. Ferrante R.J. Swartz K.J. Kowall N.W. J. Neurosci. 1991; 11: 1649-1659Crossref PubMed Google Scholar, 7Storey E. Kowall N.W. Finn S.F. Mazurek M.F. Beal M.F. Ann. Neurol. 1992; 32: 526-534Crossref PubMed Scopus (55) Google Scholar, 11Zeron M.M. Hansson O. Chen N. Wellington C.L. Leavitt B.R. Brundin P. Hayden M.R. Raymond L.A. Neuron. 2002; 33: 849-860Abstract Full Text Full Text PDF PubMed Scopus (522) Google Scholar, 12Arning L. Kraus P.H. Valentin S. Saft C. Andrich J. Epplen J.T. Neurogenetics. 2005; 6: 25-28Crossref PubMed Scopus (82) Google Scholar). In particular, there is increased sensitivity to NMDA receptor-mediated excitotoxic cell death in a YAC128 transgenic mouse model of HD (11Zeron M.M. Hansson O. Chen N. Wellington C.L. Leavitt B.R. Brundin P. Hayden M.R. Raymond L.A. Neuron. 2002; 33: 849-860Abstract Full Text Full Text PDF PubMed Scopus (522) Google Scholar) and NR2A and NR2B receptor gene variations modify the age of HD onset (12Arning L. Kraus P.H. Valentin S. Saft C. Andrich J. Epplen J.T. Neurogenetics. 2005; 6: 25-28Crossref PubMed Scopus (82) Google Scholar). More recently, Group I metabotropic glutamate receptors (mGluRs), which are G protein-coupled receptors (GPCRs) linked to the activation of phospholipase C, increase in intracellular inositol 1,4,5-triphosphate (IP3) formation, and the release of intracellular Ca2+ stores have been proposed to contribute to the underlying pathophysiology of HD. Specifically, the survival of R6/2 HD transgenic mice is significantly increased following treatment with mGluR5 antagonists (13Schiefer J. Sprunken A. Puls C. Luesse H.G. Milkereit A. Milkereit E. Johann V. Kosinski C.M. Brain Res. 2004; 1019: 246-254Crossref PubMed Scopus (97) Google Scholar). In addition, mutant Htt and Htt-associated protein 1 interactions with the IP3 receptor result in altered mGluR5-stimulated Ca2+ signaling (14Tang T.S. Tu H. Chan E.Y. Maximov A. Wang Z. Wellington C.L. Hayden M.R. Bezprozvanny I. Neuron. 2003; 39: 227-239Abstract Full Text Full Text PDF PubMed Scopus (411) Google Scholar). This increased Ca2+ release is associated with increased apoptosis of medium spiny striatal neurons derived from a YAC128 transgenic mouse model of HD (15Tang T.S. Slow E. Lupu V. Stavrovskaya I.G. Sugimori M. Llinas R. Kristal B.S. Hayden M.R. Bezprozvanny I. Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 2602-2607Crossref PubMed Scopus (319) Google Scholar). Thus, glutamate signaling via both ionotropic and metabotropic receptors may be linked with Htt function and HD. Optineurin (OPTN) is one of a number of recently identified Htt-interacting proteins (4Harjes P. Wanker E.E. Trends Biochem. Sci. 2003; 28: 425-433Abstract Full Text Full Text PDF PubMed Scopus (433) Google Scholar). OPTN is a coiled-coiled protein that was first identified as a positive regulator of tumor necrosis factor-α-mediated apoptosis (16Li Y. Kang J. Horwitz M.S. Mol. Cell. Biol. 1998; 18: 1601-1610Crossref PubMed Scopus (180) Google Scholar). OPTN interacts with a variety of proteins that link it to the regulation of cellular morphogenesis and membrane trafficking (Rab8), vesicular trafficking (Htt), and transcription activation (TFIIIA) (17Faber P.W. J. Chen J. Mol. Genet. 1998; PubMed Scopus Google Scholar, J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, R.J. Res. 28: PubMed Scopus Google Scholar). in OPTN are for of of normal glaucoma T. A. R. G. L. M. E. T. R. D. M. 2002; PubMed Scopus Google Scholar). The link between OPTN, and the observed in glaucoma has to the that OPTN may to loss T. A. R. G. L. M. E. T. R. D. M. 2002; PubMed Scopus Google Scholar). This has to the that OPTN a in neuronal cell we show that OPTN is also a Group I protein that functions to mGluR G protein to phospholipase and IP3 signaling. we show that mutant Htt not Htt the of mGluR signaling. The of OPTN with both Htt and mGluRs may an additional biochemical link that may the between neurotoxicity and HD. cells by the medium was from was from from from was from was from The with was from was from mouse and biochemical from in the used in the was from the the domain to The two gene interactions the transcription of the for in the of and of the for of the domain protein from in was by with was with and the and a of medium and and The for that to and for by a the with and a to the medium and in the and of and to and amino-terminal and GRK2 previously P.H. R. J. Biol. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, P.H. R. J. Biol. 2002; Full Text Full Text PDF PubMed Scopus (92) Google Scholar). amino-terminal Htt mutant and Htt by with by the Htt amino-terminal into with The with and The into OPTN was by a OPTN and by and of OPTN and into the of The of of the was by The for the was as The mGluR1a carboxyl-terminal was and into and to expression of amino-terminal glutathione proteins in cells, the the mGluR1a and receptor carboxyl-terminal into and P.H. Mol. Cell. Biol. 1999; 19: PubMed Scopus Google Scholar). and 293 cells and cells in medium with and The mouse striatal cell lines and mutant Htt in with a calcium phosphate Mol. Biol. 2004; Google Scholar). the cells with to for into and for an additional to and from from by the of in medium for and in a to cell medium was with and the cells with medium medium of medium with with 2 and medium of medium with 2 neurons two with HEPES-buffered saline and of the HBSS, which not neuronal in with following the M. C. P.H. J. Neurosci. 2004; PubMed Scopus Google Scholar). was a with a and with of and as previously J. Biol. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). by the cells with 1 in was by the cells with The cells for 1 in and in of the for an additional The cells in the the of of for The was by of and with of The into the cells was by the in of the cell inositol phosphate was from the cell by phosphate formation was by a of proteins from striatal cells was and mGluR5 was from striatal cell of of mGluR5 and OPTN also of cell protein from HEK 293 cells with the as in the to The cells in and with from cell by The with and proteins in and by The with in and with as as in The with and with in with and with saline and with of with the of the and analysis from of mGluR1a signaling by responses for inositol phosphate formation in HEK 293 cells with mGluR1a in the and of OPTN expression in HEK 293 the for with OPTN to mGluR1a signaling. a the of expression the of with from HEK 293 the expression of and in of HEK 293 cell the of the analysis of the of with in the of the of responses for inositol phosphate formation in HEK 293 cells that with OPTN, GRK2 and OPTN The the for C, expression of GRK2 and OPTN protein in of striatum and and HEK 293 cell The are of and mutant Htt to mGluR1a in the and of the of with a mGluR1a protein in the and of of HEK 293 cell with to OPTN expression is in these a are of of the of with in HEK 293 C, the of expression the of and with in HEK 293 is and expression in of HEK 293 The is of of and mutant Htt mGluR1a signaling. responses for inositol phosphate formation in HEK 293 cells with OPTN, and the with responses for inositol phosphate formation in HEK 293 cells with OPTN, and the with The and OPTN are the in and C, mGluR1a signaling in HEK 293 cells with OPTN, and the two with The the for of and mutant Htt mGluR1a cell expression and cell the cell expression of mGluR1a in HEK 293 cells following with and OPTN, and The the of of the of cells evidence of apoptosis following of cells with and with OPTN, and was by and was by The the of C, of cell by The of HEK 293 cells with with OPTN, and was compared with The the of inositol phosphate formation in and striatal cell the expression of OPTN, and in of from and striatal cells as as cells to OPTN, is not in HEK 293 cells of the of mGluR5 with from striatal C, for inositol phosphate formation in and striatal The the for are inositol phosphate formation in and striatal cell lines in to with and are as increase and the of nucleotide polymorphism OPTN variant in mutant Htt binding. the of and with and The is of with of OPTN and mutant expression in HEK 293 cells the of inositol phosphate formation in to treatment with in the and of The the for inositol phosphate formation in the of Htt inositol phosphate formation in the of OPTN and of and two in in a of mouse for was and with for by two in in for from the and in in was by a of by cells in medium for cells the to an was with to cells, to and cell of cells was by cell was as compared with that of the cells two in and for in two in and in for and with an a with cells as and We used to the as the number of cells compared with the number of are for the number of in the to was used to for as as to and for was by the the analysis of with the OPTN with Group I identify novel signaling proteins that interact with Group I we a the domain of mGluR1a as in the We identified OPTN as a Group I mGluR protein, and the of the was by and gene in the cells that the of with the mGluR1a domain not with the domain protein the of the we show that OPTN be co-precipitated with an mGluR1a not an protein and also be from HEK 293 cells with mGluR1a into cortical OPTN is to intracellular vesicular in both the and the and is with in these Taken together, these that interactions identified by may be OPTN mGluR1a that OPTN to Group I we OPTN interactions with mGluR1a the of the receptor to to phospholipase and in intracellular inositol phosphate We find that the of OPTN in HEK 293 cells the for inositol phosphate formation to of the for the The mechanism to the attenuation of signaling by G protein-coupled receptor Pharmacol. Rev. Google Scholar, Annu. Rev. Pharmacol. Toxicol. 1998; PubMed Scopus Google Scholar). GRK2 both agonist-stimulated and mGluR1a signaling in the of P.H. R. J. Biol. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, P.H. R. J. Biol. 2002; Full Text Full Text PDF PubMed Scopus (92) Google Scholar). is observed for OPTN expression in HEK 293 cells leads to increased mGluR1a Thus, OPTN an and novel regulator of mGluR signaling to the of agonist-stimulated mGluR GRK2 and OPTN for mGluR1a GRK2 and OPTN mGluR1a signaling by we the proteins for mGluR1a binding. We when expressed with OPTN, GRK2 OPTN to mGluR1a and is co-precipitated with the receptor In addition, the for mGluR1a inositol phosphate formation is by GRK2 to the of GRK2 is expressed with OPTN This suggests that expression GRK2 and OPTN have the of mGluR1a function. The that OPTN expression mGluR1a is to the between GRK2 and OPTN for mGluR1a binding. OPTN is expressed in and GRK2 is expressed relatively low in the striatum the region that is to neuronal in HD. GRK2 expression in the striatum are to GRK2 expression in HEK 293 cells Thus, it is that OPTN GRK2 to regulate mGluR signaling in striatal neurons. Htt with OPTN to Htt, we Htt be co-precipitated in a with mGluR1a in an We that the amino-terminal domain of Htt be with the mGluR1a in the of OPTN as a with OPTN that is with the mGluR1a The of OPTN with the mGluR1a by also with from HEK 293 cells is observed for mGluR1a OPTN expression not significantly the of mutant Htt with the we a in to following OPTN In addition, there is in the of to be with not Htt of mGluR1a of in the of OPTN not to a in the the for mGluR1a inositol phosphate formation expression the attenuation of the for mGluR1a inositol phosphate formation and the for inositol phosphate formation from to when compared with cells OPTN In the expression of mutant the increase in mGluR1a It is that the observed in mGluR1a signaling in the of OPTN and are not the of cell receptor expression increased cell death the in which we the inositol phosphate formation we that the of mGluR1a with in the and of OPTN cell cell Taken together, these that the increase in the of and OPTN with mGluR1a of mGluR1a signaling cell expression cell mGluR in from the of the attenuation of mGluR1a by OPTN, we inositol phosphate responses in striatal neuronal cell lines from mice for the knock-in of a polyglutamine expansion Htt mutant and Htt F. D. P. F. E. Mol. Genet. PubMed Scopus Google Scholar). that both cell lines of both OPTN and mGluR5 and not of by In OPTN expression is not in HEK 293 cells cells not OPTN expression in both striatal cell lines was cells to OPTN We to mGluR5 with OPTN from striatal cells with we observed in HEK 293 cells, the for inositol phosphate formation was severely impaired in the striatal cells when compared with striatal cells Specifically, the for inositol phosphate formation was by in striatal cells, and the for inositol phosphate formation in striatal cells was increased to in striatal The inositol phosphate responses following the activation of two not altered between the two cell that not a of phospholipase signaling Taken together, these that mutant Htt leads to attenuation of Group I mGluR to phospholipase and inositol phosphate Because is in HEK 293 cells following the of OPTN with mutant Htt and striatal cells relatively of OPTN we the that OPTN may with mutant Htt to mGluR signaling. OPTN in Htt OPTN gene was recently to both and for open angled glaucoma T. A. R. G. L. M. E. T. R. D. M. 2002; PubMed Scopus Google Scholar, R. A. O. A. J. Genet. 2003; PubMed Scopus Google Scholar, Chan G G E. Investig. Sci. 2004; PubMed Scopus (55) Google Scholar). We that one missense single nucleotide polymorphism OPTN with of OPTN was in we the H486R mutation of mGluR1a signaling. inositol phosphate formation in to treatment with to the as OPTN when expressed with The expression of increased of inositol phosphate formation from to of inositol phosphate responses in the of OPTN expression expression significantly the of to antagonize signaling the of these we that interactions are for the of mGluR1a signaling. In the we evidence that OPTN substitute for GRK2 to mediate the attenuation of mGluR signaling. OPTN the first protein GRK2 that the of mGluRs from G OPTN is an Htt-interacting protein that Htt may be in the regulation of mGluR signaling. expression of mutant huntingtin has mGluR1a to in inositol phosphate In when and mutant Htt are with OPTN, mutant Htt expression leads to an in OPTN to mGluR1a and increased of mGluR1a signaling. in cells derived from the striatum of knock-in mice for the expression of a Htt mGluR signaling is severely Htt to OPTN to be in the increase in G of Taken together, these that not OPTN have the capacity to substitute for GRK2 to mGluR signaling in striatal mutant Htt protein may antagonize mGluR signaling in HD. GRK2 is a ubiquitously expressed protein that is an protein that cells receptor Pharmacol. Rev. Google Scholar, Annu. Rev. Pharmacol. Toxicol. 1998; PubMed Scopus Google Scholar). GRK2 is expressed in and and expression is enhanced H. C. J. M.M. S.H. R.J. J. Biol. 1992; Full Text PDF PubMed Google Scholar). GRK2 expression are in striatal when compared with that important mechanism may be of in striatal neurons. We find that GRK2 expression in striatal is to GRK2 expression in HEK 293 cells, and we have previously that mGluR expression leads to HEK 293 cell apoptosis M. P.H. J. Biol. Full Text Full Text PDF Scopus Google Scholar). Thus, the that OPTN substitute for GRK2 to mediate the attenuation of mGluR signaling is in the striatum in which OPTN may play a role in release of Ca2+ from intracellular stores in to and mGluR signaling. OPTN is to to it is that the of mGluR signaling in the striatum is in the of mutant Htt. The that mutant Htt OPTN and mGluR desensitization was the was that Group I mGluR signaling via IP3 to intracellular Ca2+ release be to mutant Htt neurotoxicity F. Bruno V. Copani A. Casabona G. Knopfel T. Trends Neurosci. 1996; 19: 267-271Abstract Full Text Full Text PDF PubMed Scopus (406) Google Scholar, 9Calabresi P. Centonze D. Pisani A. Bernardi G. Exp. Neurol. 1999; 158: 97-108Crossref PubMed Scopus (98) Google Scholar, F. A. 1999; PubMed Scopus Google Scholar, G. F. C.L. G. F. A. D. F. J. Neurosci. 2002; PubMed Google Scholar, G. C.L. G. F. M. F. F. Bruno V. J. Neurosci. 2004; PubMed Scopus Google Scholar). Htt and Htt-associated protein 1 a with the IP3 receptor (14Tang T.S. Tu H. Chan E.Y. Maximov A. Wang Z. Wellington C.L. Hayden M.R. Bezprozvanny I. Neuron. 2003; 39: 227-239Abstract Full Text Full Text PDF PubMed Scopus (411) Google and of these proteins into medium spiny striatum neurons Ca2+ release from intracellular stores is significantly increased in to treatment with of the mGluR with of glutamate to medium spiny neurons derived from YAC128 transgenic mouse model of HD not mice also increased intracellular Ca2+ and apoptosis (15Tang T.S. Slow E. Lupu V. Stavrovskaya I.G. Sugimori M. Llinas R. Kristal B.S. Hayden M.R. Bezprozvanny I. Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 2602-2607Crossref PubMed Scopus (319) Google Scholar). The excitotoxic of glutamate in these by both Group I mGluRs and NR2B glutamate receptors. Thus, it is that the of mGluR signaling an cellular that increased IP3 receptor sensitivity in HD. studies have that single nucleotide polymorphism OPTN are associated with of normal glaucoma T. A. R. G. L. M. E. T. R. D. M. 2002; PubMed Scopus Google Scholar, R. A. O. A. J. Genet. 2003; PubMed Scopus Google Scholar, Chan G G E. Investig. Sci. 2004; PubMed Scopus (55) Google Scholar). in mGluR signaling are also in to the of glaucoma R. J. 2004; PubMed Scopus Google Scholar). it is Htt be in regulating associated with has been in both mouse and of HD, as as in a of HD D. G. S. J. D. Mol. Genet. 2002; 11: PubMed Scopus Google Scholar, I. N. P.W. Neuron. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, G. A. H. A. M. N. E. Ann. Neurol. 1993; PubMed Scopus Google Scholar). with a link between the of HD and we show here that a single nucleotide polymorphism OPTN variant linked to to bind to mutant Htt and antagonize mGluR signaling. in both mGluR signaling and OPTN function may be linked to both HD and a link between glaucoma and HD to be Group 1 mGluRs play a role in regulating neurotoxicity and F. Bruno V. G. Copani A. G. V. J. M. 1999; PubMed Scopus Google Scholar, V. G. Copani A. M.F. V. J. F. R. P.J. F. J. Neurosci. 13: Scopus Google Scholar). Thus, as the between and studies the role of mutant Htt in Ca2+ from intracellular stores be by the of mGluR signaling in HD It is that the of mGluR5 from phospholipase in striatal cells derived from mice a mechanism to altered Ca2+ in striatal neurons. be for the of Ca2+ release in cells with mutant Htt, the in IP3 formation in striatal cells is to mGluR signaling and was not observed for the increased G protein in striatal cells may the that have been for Group I Thus, a loss of may excitotoxic signaling by ionotropic glutamate receptors in HD. In the role of OPTN and mutant Htt in regulating the and signaling of mGluRs be for the of for the treatment of HD. evidence that mGluR5 is a for treatment of HD.

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