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Huntington’s Disease and Group I Metabotropic Glutamate Receptors

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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.

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Abbreviations

DHPG:

(S)-3,5-dihydroxylphenylglycine

AMPA:

Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

CNS:

Central nervous system

PLC:

Phospholipase C

ERK:

Extracellular signal-regulated kinase

MAPK:

Mitogen-activated protein kinase

GPCR:

G protein-coupled receptor

InsP:

Inositol phosphate

AD:

Alzheimer’s disease

HD:

Huntington’s disease

htt:

Huntingtin protein

IP3:

Inositol-1,4,5-triphosphate

mGluR:

Metabotropic glutamate receptor

NMDAR:

N-methyl-d-aspartate receptor

PKC:

Protein kinase C

PLCβ1:

Phospholipase Cβ1

PLD:

Phospholipase D

PLA2 :

Phospholipase A2

PI3K:

Phosphoinositide 3-kinase

PDK1:

Phosphoinositide-dependent kinase

PIKE:

PI3K enhancer

MSNs:

Medium-sized spiny neurons

PPE:

Preproenkephalin

DARPP-32:

Dopamine and cyclic AMP-regulated phosphoprotein, 32 kDa

GSK-3:

Glycogen synthase kinase-3

EC:

Endocannabinoid

BDNF:

Brain-derived neurotrophic factor

AEA:

Anandamide

2-AG:

2- arachidonoyl glycerol

TRPV1:

Transient receptor potential vanilloid 1

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Acknowledgements

S.S.G.F. holds a Tier I Canada Research Chair in Molecular Neurobiology and is a career investigator of the Heart and Stroke Foundation of Ontario. This work was supported by CIHR grant MA-15506 to S.S.G.F.

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Authors and Affiliations

  1. Departamento de Bioquimica e Imunologia, ICB, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil

    Fabiola M. Ribeiro

  2. Departamento de Ciencias Fisiologicas, CCS, Universidade Federal do Espirito Santo, Vitoria, Brazil

    Rita G. W. Pires

  3. J. Allyn Taylor Centre for Cell Biology, Molecular Brain Research Group, Robarts Research Institute and Department of Physiology and Pharmacology, University of Western Ontario, 100 Perth Drive, London, ON, Canada, N6A 5K8

    Stephen S. G. Ferguson

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  1. Fabiola M. Ribeiro
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Correspondence to Stephen S. G. Ferguson.

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Ribeiro, F.M., Pires, R.G.W. & Ferguson, S.S.G. Huntington’s Disease and Group I Metabotropic Glutamate Receptors. Mol Neurobiol 43, 1–11 (2011). https://doi.org/10.1007/s12035-010-8153-1

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