Conserved role for Ataxin‐2 in mediating endoplasmic reticulum dynamics

• Published in: Traffic (Copenhagen, Denmark) Vol. 20; no. 6; pp. 436 - 447
• Main Authors: del Castillo, Urko, Gnazzo, Megan M., Sorensen Turpin, Christopher G., Nguyen, Ken C. Q., Semaya, Emily, Lam, Yuwan, Cruz, Matthew A., Bembenek, Joshua N., Hall, David H., Riggs, Blake, Gelfand, Vladimir I., Skop, Ahna R.
• Format: Journal Article
• Language: English
• Published: Former Munksgaard John Wiley & Sons A/S 01.06.2019; Wiley Subscription Services, Inc
• Subjects: Ataxin; Ataxin‐2; ATX‐2; Axons; Cerebellum; cytokinesis; DAtx‐2; Drosophila; Embryos; Endoplasmic reticulum; Evolutionary conservation; Insects; mitosis; Morphology; Neurodegenerative diseases; Neurons; Oocytes; Phenotypes; Purkinje cells; RBPs; Ribonucleic acid; RNA; Spinocerebellar ataxia; Tubules; Ultrastructure; ATX-2; DAtx-2; RNA; Ataxin-2; RBPs; cytokinesis; mitosis; neurons; endoplasmic reticulum
• ISSN: 1398-9219; 1600-0854
• DOI: 10.1111/tra.12647

Ataxin‐2, a conserved RNA‐binding protein, is implicated in the late‐onset neurodegenerative disease Spinocerebellar ataxia type‐2 (SCA2). SCA2 is characterized by shrunken dendritic arbors and torpedo‐like axons within the Purkinje neurons of the cerebellum. Torpedo‐like axons have been described to contain displaced endoplasmic reticulum (ER) in the periphery of the cell; however, the role of Ataxin‐2 in mediating ER function in SCA2 is unclear. We utilized the Caenorhabditis elegans and Drosophila homologs of Ataxin‐2 (ATX‐2 and DAtx2, respectively) to determine the role of Ataxin‐2 in ER function and dynamics in embryos and neurons. Loss of ATX‐2 and DAtx2 resulted in collapse of the ER in dividing embryonic cells and germline, and ultrastructure analysis revealed unique spherical stacks of ER in mature oocytes and fragmented and truncated ER tubules in the embryo. ATX‐2 and DAtx2 reside in puncta adjacent to the ER in both C. elegans and Drosophila embryos. Lastly, depletion of DAtx2 in cultured Drosophila neurons recapitulated the shrunken dendritic arbor phenotype of SCA2. ER morphology and dynamics were severely disrupted in these neurons. Taken together, we provide evidence that Ataxin‐2 plays an evolutionary conserved role in ER dynamics and morphology in C. elegans and Drosophila embryos during development and in fly neurons, suggesting a possible SCA2 disease mechanism. The RNA‐binding protein, Ataxin‐2 has a conserved role controlling endoplasmic reticulum (ER) morphology and dynamics during mitosis, in the germline, and in neurons. ATX‐2/DAtx2 localizes in puncta adjacent to the ER in embryos. Electron microscopy revealed that the rough ER is forced into unique spherical stacks in the oocyte and in embryos leading to shortened and collapsed ER tubules. Disruption of ER dynamics by knocking‐down protein levels of DAtx2 in neurons recapitulates phenotypes found in advanced Spinocerebellar ataxia type‐2(SCA2) patients. We discuss potential mechanisms explaining how Ataxin‐2may regulate ER dynamics and its implications in SCA2 disease.