title: In vivo assessment of riluzole as a potential therapeutic drug for spinocerebellar ataxia type 3.
abstract: Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominantly inherited neurodegenerative disorder for which no curative therapy is available. The cause of this disease is the expansion of a CAG repeat in the so-called ATXN3 gene leading to an expanded polyglutamine stretch in the ataxin-3 protein. Although the function of ataxin-3 has been defined as a deubiquitinating enzyme, the pathogenic pathway underlying SCA3 remains to be deciphered. Besides others, also the glutamatergic system seems to be altered in SCA3. The antiglutamatergic substance riluzole has thus been suggested as a potential therapeutic agent for SCA3. To assess whether riluzole is effective in the treatment of SCA3 in vivo, we used a phenotypically well-characterized conditional mouse model previously generated by us. Treatment with 10 mg/kg riluzole in the drinking water was started when mice showed impairment in rotarod performance. Post-symptomatic treatment with riluzole carried out for a period of 10 months led to reduction of the soluble ataxin-3 level and an increase in ataxin-3 positive accumulations, but did not improve motor deficits measured by rotarod. There was also no positive effect on home cage behavior or body weight. We even observed a pronounced reduction of calbindin expression in Purkinje cells in riluzole-treated mice. Thus, long-term treatment with riluzole was not able to alleviate disease symptoms observed in transgenic SCA3 mice and should be considered with caution in the treatment of human patients. Assessing riluzole as a potential treatment for spinocerebellar ataxia type 3 (SCA3) had no beneficial, but rather a worsening effect on our transgenic SCA3 mouse model. We hypothesize that: Riluzole treatment enhanced glutamate release in ATXN3-expressing cells leading to an increased Ca(2+) influx resulting in Purkinje cell damage shown by loss of calbindin expression.
authors.affiliation: Institute of Medical Genetics and Applied Genomics and Center for Rare Diseases, University of Tuebingen, Tuebingen, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Schmidt
authors.affiliation: Institute of Medical Genetics and Applied Genomics and Center for Rare Diseases, University of Tuebingen, Tuebingen, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Schmidt
authors.affiliation: Institute of Medical Genetics and Applied Genomics and Center for Rare Diseases, University of Tuebingen, Tuebingen, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Golla
authors.affiliation: Institute of Medical Genetics and Applied Genomics and Center for Rare Diseases, University of Tuebingen, Tuebingen, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Lehmann
authors.affiliation: Institute of Medical Genetics and Applied Genomics and Center for Rare Diseases, University of Tuebingen, Tuebingen, Germany.
authors.forename: Jonasz Jeremiasz
authors.initials: JJ
authors.lastname: Weber
authors.affiliation: Institute of Medical Genetics and Applied Genomics and Center for Rare Diseases, University of Tuebingen, Tuebingen, Germany.
authors.forename: Jeannette
authors.initials: J
authors.lastname: Hübener-Schmid
authors.affiliation: Institute of Medical Genetics and Applied Genomics and Center for Rare Diseases, University of Tuebingen, Tuebingen, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Riess
mesh_terms: D000818:Animals; D000067699:Ataxin-3 / Q000235:genetics / Q000378:metabolism*; D001835:Body Weight / Q000187:drug effects / Q000235:genetics; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D064026:Calbindins / Q000378:metabolism; D004195:Disease Models, Animal; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D017827:Machado-Joseph Disease / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D011328:Prions / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D011930:Reaction Time / Q000187:drug effects / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D019782:Riluzole / Q000627:therapeutic use*; D045442:Rotarod Performance Test
chemical_list: D064026:Calbindins; D018696:Neuroprotective Agents; D011328:Prions; D012333:RNA, Messenger; D012097:Repressor Proteins; D019782:Riluzole; C092341:ATXN3 protein, human; D000067699:Ataxin-3
keywords: mouse model; polyglutamine disease; riluzole; spinocerebellar ataxia type 3