Serotonergic signalling suppresses ataxin 3 aggregation and neurotoxicity in animal models of Machado-Joseph disease

Brain. 2015 Nov;138(Pt 11):3221-37. doi: 10.1093/brain/awv262. Epub 2015 Sep 15.

Abstract

Polyglutamine diseases are a class of dominantly inherited neurodegenerative disorders for which there is no effective treatment. Here we provide evidence that activation of serotonergic signalling is beneficial in animal models of Machado-Joseph disease. We identified citalopram, a selective serotonin reuptake inhibitor, in a small molecule screen of FDA-approved drugs that rescued neuronal dysfunction and reduced aggregation using a Caenorhabditis elegans model of mutant ataxin 3-induced neurotoxicity. MOD-5, the C. elegans orthologue of the serotonin transporter and cellular target of citalopram, and the serotonin receptors SER-1 and SER-4 were strong genetic modifiers of ataxin 3 neurotoxicity and necessary for therapeutic efficacy. Moreover, chronic treatment of CMVMJD135 mice with citalopram significantly reduced ataxin 3 neuronal inclusions and astrogliosis, rescued diminished body weight and strikingly ameliorated motor symptoms. These results suggest that small molecule modulation of serotonergic signalling represents a promising therapeutic target for Machado-Joseph disease.

Keywords: ataxin 3 aggregation; selective serotonin reuptake inhibitor, citalopram; spinocerebellar ataxia type 3; therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ataxin-3 / drug effects*
  • Ataxin-3 / metabolism
  • Behavior, Animal / drug effects
  • Caenorhabditis elegans
  • Caenorhabditis elegans Proteins / drug effects*
  • Caenorhabditis elegans Proteins / metabolism
  • Citalopram / pharmacology*
  • Disease Models, Animal
  • Gliosis / metabolism*
  • Inclusion Bodies / drug effects*
  • Inclusion Bodies / metabolism
  • Inclusion Bodies / pathology
  • Locomotion / drug effects*
  • Machado-Joseph Disease / metabolism*
  • Mice
  • Mice, Transgenic
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neurons / pathology
  • Serotonin / metabolism*
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin Uptake Inhibitors / pharmacology*
  • Synaptic Transmission / drug effects

Substances

  • Caenorhabditis elegans Proteins
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin Uptake Inhibitors
  • mod-5 protein, C elegans
  • Citalopram
  • Serotonin
  • Ataxin-3
  • Atxn3 protein, mouse
  • atx-3 protein, C elegans