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Effects of flanking sequences and cellular context on subcellular behavior and pathology of mutant HTT

Chongtham, Anjalika and Bornemann, Douglas J. and Barbaro, Brett A. and Lukacsovich, Tamas and Agrawal, Namita and Syed, Adeela and Worthge, Shane and Purcell, Judith and Burke, John and Chin, Theodore M. and Marsh, J. Lawrence (2020) Effects of flanking sequences and cellular context on subcellular behavior and pathology of mutant HTT. Human Molecular Genetics, 29 (4). pp. 674-688. ISSN 0964-6906. https://resolver.caltech.edu/CaltechAUTHORS:20200122-110805513

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Abstract

Huntington’s disease (HD) is caused by an expansion of a poly glutamine (polyQ) stretch in the huntingtin protein (HTT) that is necessary to cause pathology and formation of HTT aggregates. Here we ask whether expanded polyQ is sufficient to cause pathology and aggregate formation. By addressing the sufficiency question, one can identify cellular processes and structural parameters that influence HD pathology and HTT subcellular behavior (i.e. aggregation state and subcellular location). Using Drosophila, we compare the effects of expressing mutant full-length human HTT (fl-mHTT) to the effects of mutant human HTTexon1 and to two commonly used synthetic fragments, HTT171 and shortstop (HTT118). Expanded polyQ alone is not sufficient to cause inclusion formation since full-length HTT and HTTex1 with expanded polyQ are both toxic although full-length HTT remains diffuse while HTTex1 forms inclusions. Further, inclusions are not sufficient to cause pathology since HTT171-120Q forms inclusions but is benign and co-expression of HTT171-120Q with non-aggregating pathogenic fl-mHTT recruits fl-mHTT to aggregates and rescues its pathogenicity. Additionally, the influence of sequences outside the expanded polyQ domain is revealed by finding that small modifications to the HTT118 or HTT171 fragments can dramatically alter their subcellular behavior and pathogenicity. Finally, mutant HTT subcellular behavior is strongly modified by different cell and tissue environments (e.g. fl-mHTT appears as diffuse nuclear in one tissue and diffuse cytoplasmic in another but toxic in both). These observations underscore the importance of cellular and structural context for the interpretation and comparison of experiments using different fragments and tissues to report the effects of expanded polyQ.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1093/hmg/ddaa001DOIArticle
Additional Information:© 2020 The Author(s) 2020. Published by Oxford University Press. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model). Received: 16 October 2019; Revision received: 06 December 2019; Accepted: 07 January 2020; Published: 16 January 2020. This work was submitted in partial fulfillment of the Ph.D. degree by B.A. Barbaro. Eric Li conducted and analyzed several of the experiments as part of a science project at Northwood High School, Irvine, CA. The authors gratefully acknowledge the support of the Optical Biology Core facility and the Cancer Center Support grant of the University of California, Irvine (CC grant #CA62203). Stocks obtained from the Bloomington Drosophila Stock Center (NIH P40OD018537) were used in this study. This research was supported by the CHDI foundation (HQ-44670) and the National Institute of Health (NS-45283 to JLM). Conflict of Interest Statement: None declared.
Funders:
Funding AgencyGrant Number
NIHCA62203
NIHP40OD018537
CHDI FoundationHQ-44670
NIHNS-45283
University of California, IrvineUNSPECIFIED
Subject Keywords:huntington's disease; cytoplasm; drosophila; glutamine; pathology; pathogenicity; polyglutamine; huntingtin protein
Issue or Number:4
Record Number:CaltechAUTHORS:20200122-110805513
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20200122-110805513
Official Citation:Anjalika Chongtham, Douglas J Bornemann, Brett A Barbaro, Tamas Lukacsovich, Namita Agrawal, Adeela Syed, Shane Worthge, Judith Purcell, John Burke, Theodore M Chin, J Lawrence Marsh, Effects of flanking sequences and cellular context on subcellular behavior and pathology of mutant HTT, Human Molecular Genetics, 29(4): 674-688, 2020; https://doi.org/10.1093/hmg/ddaa001
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:100836
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:22 Jan 2020 23:52
Last Modified:17 Mar 2020 18:18

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