Huntingtin subcellular localisation is regulated by Kinase signalling activity in the StHdhQ111 model of HD

Bowles, Kathryn R., Brooks, Simon P. ORCID: https://orcid.org/0000-0001-9853-6177, Dunnett, Stephen Bruce ORCID: https://orcid.org/0000-0003-1826-1578 and Jones, Lesley ORCID: https://orcid.org/0000-0002-3007-4612 2015. Huntingtin subcellular localisation is regulated by Kinase signalling activity in the StHdhQ111 model of HD. PLoS ONE 10 (12) , e0144864. 10.1371/journal.pone.0144864

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Abstract

Huntington’s disease is a neurodegenerative disorder characterised primarily by motor abnormalities, and is caused by an expanded polyglutamine repeat in the huntingtin protein. Huntingtin dynamically shuttles between subcellular compartments, and the mutant huntingtin protein is mislocalised to cell nuclei, where it may interfere with nuclear functions, such as transcription. However, the mechanism by which mislocalisation of mutant huntingtin occurs is currently unknown. An immortalised embryonic striatal cell model of HD (StHdhQ111) was stimulated with epidermal growth factor in order to determine whether the subcellular localisation of huntingtin is dependent on kinase signalling pathway activation. Aberrant phosphorylation of AKT and MEK signalling pathways was identified in cells carrying mutant huntingtin. Activity within these pathways was found to contribute to the regulation of huntingtin and mutant huntingtin localisation, as well as to the expression of immediate-early genes. We propose that altered kinase signalling is a phenotype of Huntington’s disease that occurs prior to cell death; specifically, that altered kinase signalling may influence huntingtin localisation, which in turn may impact upon nuclear processes such as transcriptional regulation. Aiming to restore the balance of activity between kinase signalling networks may therefore prove to be an effective approach to delaying Huntington’s disease symptom development and progression.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences Medicine MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Subjects:	Q Science > QH Natural history > QH426 Genetics R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Publisher:	Public Library of Science
ISSN:	1932-6203
Funders:	Wellcome Trust
Date of First Compliant Deposit:	30 March 2016
Date of Acceptance:	23 November 2015
Last Modified:	09 May 2023 21:39
URI:	https://orca.cardiff.ac.uk/id/eprint/84468

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