Transcriptional profiles for distinct aggregation states of mutant Huntingtin exon 1 protein unmask new Huntington's disease pathways

Nagaraj S. Moily, Angelique R. Ormsby, Aleksandar Stojilovic, Yasmin M. Ramdzan, Jeannine Diesch, Ross D. Hannan, Michelle S. Zajac, Anthony J. Hannan, Alicia Oshlack*, Danny M. Hatters

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)103-112
Number of pages10
JournalMolecular and Cellular Neuroscience
Volume83
DOIs
Publication statusPublished - Sep 2017
Externally publishedYes

Keywords

  • protein misfolding
  • Amyloid
  • Neurodegenerative disease
  • Huntington's disease

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