Metabotropic Glutamate Receptor-Mediated Cell Signaling Pathways Are Altered in a Mouse Model of Huntington's Disease

Abstract

Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder caused by a polyglutamine expansion in the huntingtin protein (Httthan in Hdh Q20/Q20 striatum. PKC inhibition not only brings Hdh Q111/Q111 DHPG-stimulated InsP formation to Hdh Q20/Q20 levels, but also causes an increase in neuronal cell death in Hdh Q111/Q111 neurons. However, PKC inhibition does not modify neuronal cell death in Hdh Q20/Q20 neurons, suggesting that PKC-mediated desensitization of mGluR1/5 in Hdh Q111/Q111 mice might be protective in HD. Together, these data indicate that group I mGluR-mediated signaling pathways are altered in HD and that these cell signaling adaptations could be important for striatal neurons survival.

Treatment of Huntington's Disease

“…However, why the protein causes cellular toxicity in adulthood is not well understood. There is evidence suggesting that the interaction of the group 1 metabotropic glutamate receptors and mhtt protein may be at the root of delayed onset [4].…”

What We Observe In Vivo Is Not Always What We See In Vitro: Development and Validation of 11C-JNJ-42491293, A Novel Radioligand for mGluR2

“…In particular, mGluR2 is primarily expressed presynaptically where it reduces glutamate release and protects neurons from excitotoxicity, modulates dopaminergic and adrenergic neurotransmission, and participates in synaptic plasticity. As such, mGluR2 has been implicated in the pathogenesis of several neurologic and psychiatric disorders including schizophrenia (2), addiction (3), anxiety (4), major depression (5), and neurodegeneration (6,7). The cerebral distribution of mGluR2 messenger RNA and protein has been described in rodents (8,9) and humans (10,11), with expression throughout the cortex, striatum, thalamus, and cerebellum.…”

Regulation of G protein-coupled receptor trafficking and signaling by Rab GTPases

“…29,30 As is found for Rab8-mediated desensitization of mGluR1a signaling, the attenuation of mGluR5 signaling observed in HdhQ111/ Q111 mice is also PKC-dependent. 31 This PKC-dependent attenuation of mGluR5 signaling is neuroprotective, as PKC inhibitor treatment of neurons derived from HdhQ111/Q111 mice that are treated with the mGluR1/5 selective agonist DHPG exhibit increased DHPGmediated cell death when compared with control neurons. However, neurons derived from HdhQ111/Q111 mice that lack mGluR5 expression (HdhQ111/ Q111 mice crossed with mGluR5 knockout mice) are resistant to the neurotoxic effects of the combined treatment with DHPG and a PKC inhibitor.…”