Baclofen, a GABAB receptor agonist, enhances ubiquitin-proteasome system functioning and neuronal survival in Huntington's disease model mice

Biochem Biophys Res Commun. 2014 Jan 10;443(2):706-11. doi: 10.1016/j.bbrc.2013.12.034. Epub 2013 Dec 12.

Abstract

Huntington's disease (HD) is an autosomal neurodegenerative disease. Its manifestations is selective degeneration of medium-sized spiny neurons (MSN) in the striatum. The specificity of the vulnerability of these GABAergic MSNs can be explained by abnormal protein accumulation, excitotoxicity, mitochondrial dysfunction, and failure of trophic control, among other dysfunctions. In this study, we used in vitro and in vivo models of HD to study the effects of GABAergic neuron stimulation on the cellular protein degradation machinery. We administered the GABA(B) receptor agonist, baclofen, to wild-type or mutant huntingtin-expressing striatal cells (HD19 or HD43). Chymotrypsin-like proteasome activity and cell viability were significantly increased in the mutant huntingtin-expressing striatal cells (HD43) after GABA(B) receptor agonist treatment. In addition, we systemically administered baclofen to a HD model containing the entire human huntingtin gene with 128 CAG repeats (YAC128). Chymotrypsin-like proteasome activity was significantly increased in YAC128 transgenic mice after baclofen administration. Baclofen-injected mutant YAC128 mice also showed significantly reduced numbers of ubiquitin-positive neuronal intranuclear inclusions (NIIs) in the striatum. Baclofen markedly improved behavioral abnormalities in mutant YAC128 mice as determined by the rotarod performance test. These data indicate that stimulation of GABAergic neurons with the GABAB receptor agonist, baclofen, enhances ubiquitin-proteasome system (UPS) function and cell survival in in vitro and in vivo models of HD.

Keywords: GABA(B) receptor agonist; Huntington’s disease; Neuronal survival; Ubiquitin-proteasome system.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Baclofen / pharmacology*
  • Cell Survival / drug effects
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism*
  • Corpus Striatum / pathology
  • Disease Models, Animal*
  • GABA-B Receptor Agonists / pharmacology
  • GABAergic Neurons / cytology
  • GABAergic Neurons / drug effects
  • GABAergic Neurons / metabolism*
  • Humans
  • Huntington Disease / metabolism*
  • Huntington Disease / pathology*
  • Male
  • Mice
  • Ubiquitin-Protein Ligase Complexes / metabolism*

Substances

  • GABA-B Receptor Agonists
  • Ubiquitin-Protein Ligase Complexes
  • Baclofen