Karyopherin α-3 is a key protein in the pathogenesis of spinocerebellar ataxia type 3 controlling the nuclear localization of ataxin-3

Proceedings of the National Academy of Sciences of the United States of America
Anna Sergeevna SowaThorsten Schmidt

Abstract

Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disorder caused by a CAG expansion in the ATXN3 gene leading to a polyglutamine expansion in the ataxin-3 protein. The nuclear presence and aggregation of expanded ataxin-3 are critical steps in disease pathogenesis. To identify novel therapeutic targets, we investigated the nucleocytoplasmic transport system by screening a collection of importins and exportins that potentially modulate this nuclear localization. Using cell, Drosophila, and mouse models, we focused on three transport proteins, namely, CRM1, IPO13, KPNA3, and their respective Drosophila orthologs Emb, Cdm, and Kap-α3. While overexpression of CRM1/Emb demonstrated positive effects in Drosophila, KPNA3/Kap-α3 emerged as the most promising target, as knockdown via multiple RNAi lines demonstrated its ability to shuttle both truncated and full-length expanded ataxin-3, rescue neurodegeneration, restore photoreceptor formation, and reduce aggregation. Furthermore, KPNA3 knockout in SCA3 mice resulted in an amelioration of molecular and behavioral disturbances such as total activity, anxiety, and gait. Since KPNA3 is known to function as an import protein and recognize nuclear localization signals (NLSs), thi...Continue Reading

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Citations

Nov 21, 2018·The Journal of Biological Chemistry·Daniel WeishäuplThorsten Schmidt
Dec 24, 2018·Human Molecular Genetics·Jana SchmidtThorsten Schmidt
May 28, 2019·Journal of Neuroscience Research·Stefano Benvegnù
Dec 14, 2019·Antioxidants & Redox Signaling·Shenae Louise CafeElizabeth Grace Bromfield
Aug 15, 2020·Science·Letizia MarvaldiMike Fainzilber
Nov 25, 2018·Cells·Friederike K Kosyna, Reinhard Depping
Jun 26, 2020·Frontiers in Neuroscience·Davin LeeSung Bae Lee
Jul 4, 2020·Translational Neurodegeneration·Giacomo Bitetto, Alessio Di Fonzo
Mar 21, 2021·Molecular Brain·Anna S SowaThorsten Schmidt
Apr 4, 2021·International Journal of Molecular Sciences·Youngpyo NamSang Ryong Kim
Sep 27, 2021·Annals of Neurology·Claudia SchobJonas Denecke
May 22, 2021·Brain : a Journal of Neurology·Terouz PashaFrank Hirth

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