RNP-Granule Assembly via Ataxin-2 Disordered Domains Is Required for Long-Term Memory and Neurodegeneration

Neuron
Baskar BakthavachaluMani Ramaswami

Abstract

Human Ataxin-2 is implicated in the cause and progression of amyotrophic lateral sclerosis (ALS) and type 2 spinocerebellar ataxia (SCA-2). In Drosophila, a conserved atx2 gene is essential for animal survival as well as for normal RNP-granule assembly, translational control, and long-term habituation. Like its human homolog, Drosophila Ataxin-2 (Atx2) contains polyQ repeats and additional intrinsically disordered regions (IDRs). We demonstrate that Atx2 IDRs, which are capable of mediating liquid-liquid phase transitions in vitro, are essential for efficient formation of neuronal mRNP assemblies in vivo. Remarkably, ΔIDR mutants that lack neuronal RNP granules show normal animal development, survival, and fertility. However, they show defects in long-term memory formation/consolidation as well as in C9ORF72 dipeptide repeat or FUS-induced neurodegeneration. Together, our findings demonstrate (1) that higher-order mRNP assemblies contribute to long-term neuronal plasticity and memory, and (2) that a targeted reduction in RNP-granule formation efficiency can alleviate specific forms of neurodegeneration.

Citations

Nov 9, 2018·Current Neurology and Neuroscience Reports·Ioana DobraLoic Hamon
Jul 27, 2018·The Journal of Biological Chemistry·Edward Gomes, James Shorter
Aug 23, 2019·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Polina A Egorova, Ilya B Bezprozvanny
Feb 23, 2020·The FEBS Journal·Anna Bratek-SkickiPeter Tompa
May 24, 2020·Wiley Interdisciplinary Reviews. RNA·Nisansala S MuthunayakeJared M Schrader
Jun 15, 2019·Nature Communications·Jeshlee VijayakumarFlorence Besse
Mar 21, 2019·Nature Reviews. Neurology·Natalia B Nedelsky, J Paul Taylor
Feb 3, 2019·Cold Spring Harbor Perspectives in Biology·Briana Van Treeck, Roy Parker
Jul 25, 2019·Scientific Reports·Svetlana PiatnitskaiaMasahiro Fujii
Oct 7, 2020·Proceedings of the National Academy of Sciences of the United States of America·Gábor M HaramiMihály Kovács
Oct 29, 2020·Biophysics and Physicobiology·Takuya Yoshizawa, Hiroyoshi Matsumura
Oct 14, 2020·Mechanisms of Ageing and Development·Amr OmerImed-Eddine Gallouzi
Sep 26, 2020·Journal of Molecular Cell Biology·Donya PakravanLudo Van Den Bosch
Oct 7, 2020·Trends in Genetics : TIG·Fabio PessinaFabrizio d'Adda di Fagagna
Jan 31, 2020·Molecular Cell·Thomas Gonatopoulos-PournatzisBenjamin J Blencowe
Apr 4, 2021·International Journal of Molecular Sciences·Zaira M López-JuárezPlinio Guzmán
Apr 17, 2021·Frontiers in Behavioral Neuroscience·Camilla RoselliIsaac Cervantes-Sandoval
May 11, 2021·Frontiers in Cellular Neuroscience·Daniel A SolomonSarah Mizielinska
Jun 19, 2021·Computational and Structural Biotechnology Journal·Elisa FlorisCarlo C Campa
Jul 30, 2021·Cellular and Molecular Life Sciences : CMLS·Francesco LiguoriCinzia Volonté
Sep 1, 2020·Journal of Proteome Research·Anna A KliuchnikovaSergei A Moshkovskii
Oct 10, 2018·Journal of Proteome Research·Ksenia G KuznetsovaSergei A Moshkovskii
Feb 8, 2021·Biochimica Et Biophysica Acta. Molecular Cell Research·April L Darling, James Shorter

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