Transcriptional profiles for distinct aggregation states of mutant Huntingtin exon 1 protein unmask new Huntington's disease pathways
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Moily, Nagaraj S.; Ormsby, Angelique R.; Stojilovic, Aleksandar; Ramdzan, Yasmin M.; Diesch, Jeannine; Hannan, Ross D.; Zajac, Michelle S.; Hannan, Anthony J.; Oshlack, Alicia; Hatters, Danny M.
Description
Huntington's disease is caused by polyglutamine (polyQ)-expansion mutations in the CAG tandem repeat of the Huntingtin gene. The central feature of Huntington's disease pathology is the aggregation of mutant Huntingtin (Htt) protein into micrometer-sized inclusion bodies. Soluble mutant Htt states are most proteotoxic and trigger an enhanced risk of death whereas inclusions confer different changes to cellular health, and may even provide adaptive responses to stress. Yet the molecular...[Show more]
dc.contributor.author | Moily, Nagaraj S. | |
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dc.contributor.author | Ormsby, Angelique R. | |
dc.contributor.author | Stojilovic, Aleksandar | |
dc.contributor.author | Ramdzan, Yasmin M. | |
dc.contributor.author | Diesch, Jeannine | |
dc.contributor.author | Hannan, Ross D. | |
dc.contributor.author | Zajac, Michelle S. | |
dc.contributor.author | Hannan, Anthony J. | |
dc.contributor.author | Oshlack, Alicia | |
dc.contributor.author | Hatters, Danny M. | |
dc.date.accessioned | 2018-01-03T04:32:11Z | |
dc.identifier.issn | 1044-7431 | |
dc.identifier.uri | http://hdl.handle.net/1885/139047 | |
dc.description.abstract | Huntington's disease is caused by polyglutamine (polyQ)-expansion mutations in the CAG tandem repeat of the Huntingtin gene. The central feature of Huntington's disease pathology is the aggregation of mutant Huntingtin (Htt) protein into micrometer-sized inclusion bodies. Soluble mutant Htt states are most proteotoxic and trigger an enhanced risk of death whereas inclusions confer different changes to cellular health, and may even provide adaptive responses to stress. Yet the molecular mechanisms underpinning these changes remain unclear. Using the flow cytometry method of pulse-shape analysis (PulSA) to sort neuroblastoma (Neuro2a) cells enriched with mutant or wild-type Htt into different aggregation states, we clarified which transcriptional signatures were specifically attributable to cells before versus after inclusion assembly. Dampened CREB signalling was the most striking change overall and invoked specifically by soluble mutant Httex1 states. Toxicity could be rescued by stimulation of CREB signalling. Other biological processes mapped to different changes before and after aggregation included NF-kB signalling, autophagy, SUMOylation, transcription regulation by histone deacetylases and BRD4, NAD+ biosynthesis, ribosome biogenesis and altered HIF-1 signalling. These findings open the path for therapeutic strategies targeting key molecular changes invoked prior to, and subsequently to, Httex1 aggregation. | |
dc.description.sponsorship | This work was supported by grants to DMH from the Australian Research Council (grant number FT120100039); grants/fellowships from the National Health and Medical Research Council Project to DMH (grant numbers APP1049458, APP1049459 and APP1102059), and a grant from the Hereditary Disease Foundation (USA). AJH is an NHMRC Principal Research Fellow. | |
dc.format.mimetype | application/pdf | |
dc.publisher | Elsevier | |
dc.rights | © 2017 Elsevier Inc. | |
dc.source | Molecular and cellular neurosciences | |
dc.subject | amyloid | |
dc.subject | huntington's disease | |
dc.subject | neurodegenerative disease | |
dc.subject | protein misfolding | |
dc.title | Transcriptional profiles for distinct aggregation states of mutant Huntingtin exon 1 protein unmask new Huntington's disease pathways | |
dc.type | Journal article | |
local.identifier.citationvolume | 83 | |
dc.date.issued | 2017-09 | |
local.publisher.url | https://www.elsevier.com/ | |
local.type.status | Accepted Version | |
local.contributor.affiliation | Hannan, R., The John Curtin School of Medical Research, Australian National University | |
dc.relation | http://purl.org/au-research/grants/arc/FT120100039 | |
dc.relation | http://purl.org/au-research/grants/nhmrc/1049458 | |
dc.relation | http://purl.org/au-research/grants/nhmrc/1049459 | |
dc.relation | http://purl.org/au-research/grants/nhmrc/1102059 | |
local.identifier.essn | 1095-9327 | |
local.bibliographicCitation.startpage | 103 | |
local.bibliographicCitation.lastpage | 112 | |
local.identifier.doi | 10.1016/j.mcn.2017.07.004 | |
dcterms.accessRights | Open Access | |
dc.provenance | http://www.sherpa.ac.uk/romeo/issn/1044-7431/..."Author's post-print on open access repository after an embargo period of between 12 months and 48 months" from SHERPA/RoMEO site (as at 3/01/18). | |
Collections | ANU Research Publications |
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