A role of cellular translation regulation associated with toxic Huntingtin protein
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Cellular and Molecular Life Sciences
ORIGINAL ARTICLE
A role of cellular translation regulation associated with toxic Huntingtin protein Hiranmay Joag1,3 · Vighnesh Ghatpande1 · Meghal Desai1 · Maitheli Sarkar1 · Anshu Raina1 · Mrunalini Shinde2 · Ruta Chitale2 · Ankita Deo2 · Tania Bose2 · Amitabha Majumdar1 Received: 7 July 2019 / Revised: 19 November 2019 / Accepted: 22 November 2019 © Springer Nature Switzerland AG 2019
Abstract Huntington’s disease (HD) is a severe neurodegenerative disorder caused by poly Q repeat expansion in the Huntingtin (Htt) gene. While the Htt amyloid aggregates are known to affect many cellular processes, their role in translation has not been addressed. Here we report that pathogenic Htt expression causes a protein synthesis deficit in cells. We find a functional prionlike protein, the translation regulator Orb2, to be sequestered by Htt aggregates in cells. Co-expression of Orb2 can partially rescue the lethality associated with poly Q expanded Htt. These findings can be relevant for HD as human homologs of Orb2 are also sequestered by pathogenic Htt aggregates. Our work suggests that translation dysfunction is one of the contributors to the pathogenesis of HD and new therapies targeting protein synthesis pathways might help to alleviate disease symptoms. Keywords Huntington’s disease · Functional-prion-like protein · Translation regulator · Orb2
Introduction Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder with no known treatment till date [1]. The symptoms associated with the disease include severe motor defects such as chorea and uncoordinated movements along with cognitive and behavioral problems that are progressive in nature. In the human brain, HD phenotypes are Hiranmay Joag, Vighnesh Ghatpande, Meghal Desai, Maitheli Sarkar, Anshu Raina and Mrunalini Shinde have contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00018-019-03392-y) contains supplementary material, which is available to authorized users. * Tania Bose [email protected] * Amitabha Majumdar [email protected] 1
National Centre for Cell Science, S. P. Pune University, Pune, India
2
Institute of Bioinformatics and Biotechnology, S. P. Pune University, Pune, India
3
Present Address: Max Planck Institute of Neurobiology, Martinsried, Germany
manifested as severe atrophy of the caudate nucleus and putamen regions which together are part of the dorsal striatum. While the adult-onset HD phenotypes start manifesting after 40 years of age, there are also cases of juvenile HD which begin manifesting at very early ages and are more aggressive in nature [2]. HD is caused by the expansion of CAG repeats in Exon1 of the Huntingtin gene on chromosome 4p16 [3]. The CAG triplet codes for Glutamine (Q) and disease-causing expansions can range from approximately 40–200 [4]. Due to polyQ expansion, the expanded Huntingtin (Htt) protein forms misfolded aggregates causing an imbalance in cellul
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