Transcriptional profiles for distinct aggregation states of mutant Huntingtin exon 1 protein unmask new Huntington's disease pathways
| Autor: | Ross D. Hannan, Angelique R. Ormsby, Aleksandar Stojilovic, Alicia Oshlack, Anthony J. Hannan, Danny M. Hatters, Yasmin M. Ramdzan, Jeannine Diesch, Michelle S. Zajac, Nagaraj S. Moily |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
congenital hereditary and neonatal diseases and abnormalities Amyloid Huntingtin SUMO protein Protein aggregation CREB Neurodegenerative disease Protein Aggregation Pathological 03 medical and health sciences Cellular and Molecular Neuroscience Mice Huntington's disease Cell Line Tumor mental disorders medicine Huntingtin Protein Transcriptional regulation Animals 10. No inequality Cyclic AMP Response Element-Binding Protein Molecular Biology Genetics biology Neurodegeneration Cell Biology Exons medicine.disease 030104 developmental biology Huntington Disease Mutation biology.protein Transcriptome Protein misfolding Signal Transduction |
| Zdroj: | MOLECULAR AND CELLULAR NEUROSCIENCE r-IGTP. Repositorio Institucional de Producción Científica del Instituto de Investigación Germans Trias i Pujol instname |
| ISSN: | 1095-9327 1044-7431 |
| Popis: | 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 (Pu1SA) 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 Httexl 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, Httexl aggregation. |
| Databáze: | OpenAIRE |
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