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DJ-1 modulates aggregation and pathogenesis in models of Huntington’s disease

Sajjad, Muhammad U. and Green, Edward W. and Miller-Fleming, Leonor and Hands, Sarah and Herrera, Federico and Campesan, Susanna and Kroshnan, Ali and Outeiro, Triago F. and Giorgini, Flaviano and Wyttenbach, Andreas (2014) DJ-1 modulates aggregation and pathogenesis in models of Huntington’s disease. Human Molecular Genetics, 23 (3). pp. 755-766. ISSN 0964-6906.

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The oxidation-sensitive chaperone protein DJ-1 has been implicated in several human disorders including cancer and neurodegenerative diseases. During neurodegeneration associated with protein misfolding, such as that observed in Alzheimer's disease and Huntington's disease (HD), both oxidative stress and protein chaperones have been shown to modulate disease pathways. Therefore, we set out to investigate whether DJ-1 plays a role in HD. We found that DJ-1 expression and its oxidation state are abnormally increased in the human HD brain, as well as in mouse and cell models of HD. Furthermore, overexpression of DJ-1 conferred protection in vivo against neurodegeneration in yeast and Drosophila. Importantly, the DJ-1 protein directly interacted with an expanded fragment of huntingtin Exon 1 (httEx1) in test tube experiments and in cell models and accelerated polyglutamine aggregation and toxicity in an oxidation-sensitive manner. Our findings clearly establish DJ-1 as a potential therapeutic target for HD and provide the basis for further studies into the role of DJ-1 in protein misfolding diseases.

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Additional Information:© 2013 The Author. Published by Oxford University Press. Received June 19, 2013; Revised and Accepted September 19, 2013. First published online: September 26, 2013. We thank Richard Faull (University of Auckland, New Zealand) for provision of the human brain tissue and express our appreciation to the Huntington’s disease families of New Zealand for the generous bequest of tissue for research purposes. The human brain tissue was obtained from the New Zealand Neurological Foundation Human Brain Bank with ethical approval from the University of Auckland Human Participants Ethical Committee. We also thank A.J. Morton (University of Cambridge, UK) for provision of the mouse tissue and L. Jones (Cardiff University, UK) for help with the storage and extraction of the human brain tissue. Thanks also go to Charalambos P. Kyriacou (University of Leicester, UK) for advice with the Drosophila work. Many thanks go to Vincent O’Connor (University of Southampton, UK) for constant intellectual support and stimulation and fruitful discussions on the DJ-1 project. We would also like to acknowledge Prof. Hiroyoshi Ariga (Hokkaido University, Japan) for sending us the Cys106S construct. Funding: This work was supported by the Medical Research Trust (A.W.), the Gerald Kirkut Trust (Southampton, UK) (M.U.S.), the Bestway Foundation (UK) (M.U.S.), the University of Southampton (UK) (M.U.S.) and the CHDI Foundation, Inc. (F.G.). Conflict of Interest statement. None declared.
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Medical Research TrustUNSPECIFIED
Gerald Kirkut Trust (Southampton, UK)UNSPECIFIED
Bestway Foundation (UK)UNSPECIFIED
University of Southampton (UK)UNSPECIFIED
Issue or Number:3
Record Number:CaltechAUTHORS:20140318-114050128
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Official Citation: Muhammad U. Sajjad, Edward W. Green, Leonor Miller-Fleming, Sarah Hands, Federico Herrera, Susanna Campesan, Ali Khoshnan, Tiago F. Outeiro, Flaviano Giorgini, and Andreas Wyttenbach DJ-1 modulates aggregation and pathogenesis in models of Huntington's disease Hum. Mol. Genet. (2014) 23 (3): 755-766 first published online September 26, 2013 doi:10.1093/hmg/ddt466
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:44380
Deposited By: Ruth Sustaita
Deposited On:18 Mar 2014 20:23
Last Modified:03 Oct 2019 06:17

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