T1-11 and JMF1907 ameliorate polyglutamine-expanded ataxin-3-induced neurodegeneration, transcriptional dysregulation and ataxic symptom in the SCA3 transgenic mouse

Neuropharmacology. 2015 Dec:99:308-17. doi: 10.1016/j.neuropharm.2015.08.009. Epub 2015 Aug 6.

Abstract

More studies are required to develop therapeutic agents for treating spinocerebellar ataxia type 3 (SCA3), which is caused by mutant polyglutamine-expanded ataxin-3 and is the most prevalent subtype of spinocerebellar ataxias. T1-11 [N6-(4-Hydroxybenzyl) adenosine], isolated from a Chinese medicinal herb Gastordia elata, is an adenosine A2A receptor agonist. SCA3 and Huntington's disease (HD) belong to a family of polyglutamine neurodegenerative diseases. T1-11 exerted a therapeutic effect on HD transgenic mouse by decreasing protein level of polyglutamine-expanded huntingtin in the striatum. In the present study, we test the possibility that T1-11 or JMF1907 [N6-(3-Indolylethyl) adenosine], a synthetic analog of T1-11, alleviates pontine neuronal death, cerebellar transcriptional downregulation and ataxic symptom in the SCA3 transgenic mouse expressing HA-tagged polyglutamine-expanded ataxin-3-Q79 (ataxin-3-Q79HA). Daily oral administration of T1-11 or JMF1907 prevented neuronal death of pontine nuclei in the SCA3 mouse with a dose-dependent manner. Oral application of T1-11 or JMF1907 reversed mutant ataxin-3-Q79-induced cerebellar transcriptional repression in the SCA3 transgenic mouse. T1-11 or JMF1907 ameliorated the symptom of motor incoordination displayed by SCA3 mouse. Oral administration of T1-11 or JMF1907 significantly decreased protein level of ataxin-3-Q79HA in the pontine nuclei or cerebellum of SCA3 mouse. T1-11 or JMF1907 significantly augmented the chymotrypsin-like activity of proteasome in the pontine nuclei or cerebellum of SCA3 mouse. Our results suggests that T1-11 and JMF1907 alleviate pontine neuronal death, cerebellar transcriptional downregulation and ataxic symptom of SCA3 transgenic mouse by augmenting the proteasome activity and reducing the protein level of polyglutamine-expanded ataxin-3-Q79 in the pontine nuclei and cerebellum.

Keywords: Cerebellum; JMF1907; Polyglutamine-expanded ataxin-3; Pontine nuclei; SCA3; SCA3 transgenic mice; T1-11.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / pharmacology
  • Administration, Oral
  • Animals
  • Ataxin-3 / genetics
  • Ataxin-3 / metabolism
  • Caspase 3 / metabolism
  • Caspase 9 / metabolism
  • Cell Death / drug effects
  • Cell Death / physiology
  • Cerebellum / drug effects
  • Cerebellum / metabolism
  • Cerebellum / pathology
  • Dose-Response Relationship, Drug
  • Down-Regulation / drug effects
  • Humans
  • Indoles / pharmacology*
  • Machado-Joseph Disease / drug therapy*
  • Machado-Joseph Disease / pathology
  • Machado-Joseph Disease / physiopathology
  • Mice, Transgenic
  • Motor Activity / drug effects
  • Motor Activity / physiology
  • Neurons / drug effects
  • Neurons / pathology
  • Neuroprotective Agents / pharmacology*
  • Pons / drug effects
  • Pons / metabolism
  • Pons / pathology
  • Proteasome Endopeptidase Complex / metabolism
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • bcl-2-Associated X Protein / metabolism
  • bcl-X Protein / metabolism

Substances

  • Bax protein, mouse
  • Bcl2l1 protein, mouse
  • Indoles
  • N6-(3-indolylethyl)adenosine
  • N6-(4-hydroxybenzyl)adenosine
  • Neuroprotective Agents
  • Repressor Proteins
  • bcl-2-Associated X Protein
  • bcl-X Protein
  • ATXN3 protein, human
  • Ataxin-3
  • Casp3 protein, mouse
  • Casp9 protein, mouse
  • Caspase 3
  • Caspase 9
  • Proteasome Endopeptidase Complex
  • Adenosine