Huntington’s Disease and Group I Metabotropic Glutamate Receptors

Abstract

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized by involuntary body movement, cognitive impairment and psychiatric disturbance. A polyglutamine expansion in the amino-terminal region of the huntingtin (htt) protein is the genetic cause of HD. Htt protein interacts with a wide variety of proteins, and htt mutation causes cell signaling alterations in various neurotransmitter systems, including dopaminergic, glutamatergic, and cannabinoid systems, as well as trophic factor systems. This review will overview recent findings concerning htt-promoted alterations in cell signaling that involve different neurotransmitters and trophic factor systems, especially involving mGluR1/5, as glutamate plays a crucial role in neuronal cell death. The neuronal cell death that takes place in the striatum and cortex of HD patients is the most important factor underlying HD progression. Metabotropic glutamate receptors (mGluR1 and mGluR5) have a very controversial role in neuronal cell death and it is not clear whether mGluR1/5 activation either protects or exacerbates neuronal death. Thus, understanding how mutant htt protein affects glutamatergic receptor signaling will be essential to further establish a role for glutamate receptors in HD and develop therapeutic strategies to treat HD.

Selective expression of mutant huntingtin during development recapitulates characteristic features of Huntington’s disease

“…These findings suggest that alterations in CBR1 or other components of the signaling pathways of striatal LTD could contribute to the corticostriatal plasticity defects in HD. Accordingly, patients with HD and mouse models display alterations in molecular components of striatal LTD, including cannabinoid receptors (38)(39)(40) and the mGluR5 signaling pathway (41)(42)(43). Previous studies have shown that using an agonist for CBR1 (WIN 55,212-2) (44) or mGluR5 (42,45) modulators in HD mouse models ameliorates several alterations associated with corticostriatal dysfunction.…”

Involvement of metabotropic glutamate receptor 5, AKT/PI3K Signaling and NF-κB pathway in methamphetamine-mediated increase in IL-6 and IL-8 expression in astrocytes

“…Furthermore, we sought to investigate a link between the effects of MA on mGluR5 and NF-κB activation. Since the classical Huntington's disease pathway involves activation of the Akt/PI3K pathway, which is mediated via the mGluR5 receptor [54], we hypothesized a role for Akt/PI3K in the signaling cascade induced by MA. Our results support this hypothesis, because the antagonist for Akt/PI3K abrogated MA-mediated expression of IL-6 and IL-8.…”

The Function of Metabotropic Glutamate Receptors in Thalamus and Cortex

“…In some cases, specific roles for mGluRs have been suggested, such as abnormal LTD production in fragile X syndrome (Bear and others 2004; Goebel-Goody and Lombroso 2012; Zhang and Alger 2010), and group I mGluR involvement in endocannabinoid control of synaptic processing in schizophrenia and addiction (Melis and others 2004), but for the most part, the actual role of mGluRs in various diseases remains to be elucidated or even suggested. Cognitive diseases that have been so far implicated with regard to mGluR functioning include schizophrenia, anxiety disorders, mental retardation, fragile X syndrome and autism, Alzheimer's, Parkinson's, Huntingdon's, anxiety, depression, addiction, and epilepsy (Alexander and Godwin 2006a; Harrison and others 2008; Huang and others 2007; Luscher and Huber 2010; Marek 2010; Ribeiro and others 2011; Tamminga 2006; Ure and others 2006; Wong and others 1999). …”