Expanded ATXN3 frameshifting events are toxic in Drosophila and mammalian neuron models

Human Molecular Genetics
Shawn J StochmanskiGuy A Rouleau

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.

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Citations

Aug 7, 2013·Human Molecular Genetics·John D Cleary, Laura P W Ranum
Oct 2, 2014·Proceedings of the National Academy of Sciences of the United States of America·Hyun Jin KwunYuan Chang
Sep 14, 2014·Nucleic Acids Research·Marzena WojciechowskaWlodzimierz J Krzyzosiak
Jul 16, 2015·Journal of Neurogenetics·Chia-Rung Liu, Tzu-Hao Cheng
Nov 22, 2015·Neuron·Monica Bañez-CoronelLaura P W Ranum
Apr 10, 2016·Brain Research·Katelyn M GreenPeter K Todd
Aug 12, 2015·Nature Reviews. Genetics·Pavel V BaranovMartina M Yordanova
Apr 16, 2015·Mediators of Inflammation·Marta OlejniczakWlodzimierz J Krzyzosiak
May 23, 2014·Nucleic Acids Research·Agnieszka Fiszer, Wlodzimierz J Krzyzosiak
May 7, 2016·Nature Reviews. Neuroscience·Aaron R HaeuslerJeffrey D Rothstein
Oct 25, 2016·Frontiers in Cellular Neuroscience·Nadine GriescheSybille Krauss
Jul 7, 2016·The Journal of Biological Chemistry·Paul SaffertZoya Ignatova
Feb 8, 2020·Proceedings of the National Academy of Sciences of the United States of America·Su YangXiao-Jiang Li
Jul 14, 2020·Current Opinion in Neurology·Maria do Carmo Costa
Mar 18, 2021·Biochemical Society Transactions·Lydia M CastelliGuillaume M Hautbergue
Nov 7, 2020·Journal of Molecular Biology·Magdalena Jazurek-CiesiolkaAgnieszka Fiszer
Jun 19, 2021·Nature Reviews. Molecular Cell Biology·Indranil MalikPeter K Todd
Jun 3, 2021·Human Molecular Genetics·Leeanne McGurkNancy M Bonini

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