title: Expanded ATXN3 frameshifting events are toxic in Drosophila and mammalian neuron models.
abstract: Spinocerebellar ataxia type 3 is caused by the expansion of the coding CAG repeat in the ATXN3 gene. Interestingly, a -1 bp frameshift occurring within an (exp)CAG repeat would henceforth lead to translation from a GCA frame, generating polyalanine stretches instead of polyglutamine. Our results show that transgenic expression of (exp)CAG ATXN3 led to -1 frameshifting events, which have deleterious effects in Drosophila and mammalian neurons. Conversely, transgenic expression of polyglutamine-encoding (exp)CAA ATXN3 was not toxic. Furthermore, (exp)CAG ATXN3 mRNA does not contribute per se to the toxicity observed in our models. Our observations indicate that expanded polyglutamine tracts in Drosophila and mouse neurons are insufficient for the development of a phenotype. Hence, we propose that -1 ribosomal frameshifting contributes to the toxicity associated with (exp)CAG repeats.
authors.affiliation: Center of Excellence in Neuroscience of the Université de Montréal (CENUM), Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, Québec, Canada.
authors.forename: Shawn J
authors.initials: SJ
authors.lastname: Stochmanski
authors.forename: Martine
authors.initials: M
authors.lastname: Therrien
authors.forename: Janet
authors.initials: J
authors.lastname: Laganière
authors.forename: Daniel
authors.initials: D
authors.lastname: Rochefort
authors.forename: Sandra
authors.initials: S
authors.lastname: Laurent
authors.forename: Liliane
authors.initials: L
authors.lastname: Karemera
authors.forename: Rebecca
authors.initials: R
authors.lastname: Gaudet
authors.forename: Kishanda
authors.initials: K
authors.lastname: Vyboh
authors.forename: Don J
authors.initials: DJ
authors.lastname: Van Meyel
authors.forename: Graziella
authors.initials: G
authors.lastname: Di Cristo
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Dion
authors.forename: Claudia
authors.initials: C
authors.lastname: Gaspar
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000067699:Ataxin-3; D004330:Drosophila / Q000235:genetics* / Q000378:metabolism; D018965:Frameshifting, Ribosomal; D007150:Immunohistochemistry; D017827:Machado-Joseph Disease / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D012333:RNA, Messenger / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D019680:Trinucleotide Repeat Expansion
chemical_list: D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D012333:RNA, Messenger; D014157:Transcription Factors; C019529:polyalanine; D000067699:Ataxin-3; C511594:Atxn3 protein, mouse