Misfolded polyglutamine, polyalanine, and superoxide dismutase 1 aggregate via distinct pathways in the cell
AuthorPolling, Saskia; MOK, YEE-FOONG; Ramdzan, Yasmin M.; Turner, Bradley J.; Yerbury, Justin J.; Hill, Andrew F.; Hatters, Danny M.
Source TitleJournal of Biological Chemistry
PublisherAmerican Society for Biochemistry and Molecular Biology
University of Melbourne Author/sPolling, Saskia; Mok, Yee-Foong; RAMDZAN, YASMIN MOHAMED; Turner, Bradley; Hill, Andrew; Hatters, Daniel
AffiliationDepartment of Biochemistry and Molecular Biology
Bio21 Molecular Science and Biotechnology Institute
Florey Institute of Neuroscience and Mental Health
Centre for Neuroscience
Biochemistry and Molecular Biology
Centre for Neuroscience
Document TypeJournal Article
CitationsPolling, S., Mok, Y-F., Ramdzan, Y. M., Turner, B. J., Yerbury, J. J., Hill, A. F., et al. (2014). Misfolded polyglutamine, polyalanine, and superoxide dismutase 1 aggregate via distinct pathways in the cell. Journal of Biological Chemistry, 289(10), 6669-6680.
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© 2014 by The American Society for Biochemistry and Molecular Biology
The research outputs in this collection have been funded in whole or in part by the National Health and Medical Research Council (NHMRC).
Protein aggregation into intracellular inclusions is a key feature of many neurodegenerative disorders. A common theme has emerged that inappropriate selfaggregation of misfolded or mutant polypeptide sequences is detrimental to cell health. Yet protein quality control mechanisms may also deliberately cluster them together into distinct inclusion sub-types, including the insoluble protein deposit (IPOD) and the juxtanuclear quality control (JUNQ). Here we investigated how the intrinsic oligomeric state of three model systems of disease-relevant mutant protein and peptide sequences relates to the IPOD and JUNQ patterns of aggregation using sedimentation velocity analysis (SVA). Two of the models (polyalanine (37A) and superoxide dismutase 1 (SOD1) mutants A4V and G85R) accumulated into the same JUNQ-like inclusion whereas the other, polyglutamine (72Q), formed spatially distinct IPOD-like inclusions. Using flow cytometry pulse shape analysis to separate cells with inclusions from those without revealed the SOD1 mutants and 37A to have abruptly altered oligomeric states with respect to the non-aggregating forms, regardless of whether cells had inclusions or not; whereas 72Q was almost exclusively monomeric until inclusions formed. We propose mutations leading to JUNQ inclusions induce a constitutively "misfolded" state exposing hydrophobic sidechains that attract and ultimately overextend protein quality capacity, which leads to aggregation into JUNQ inclusions. PolyQ is not "misfolded" in this same sense due to universal polar sidechains, but is highly prone to forming amyloid fibrils that we propose invoke a different engagement mechanism with quality control.
Keywordsaggregation; inclusion; amyotrophic lateral sclerosis (Lou Gehrig's disease); superoxide dismutase (SOD1); polyalanine; polyglutamine; analytical ultracentrifugation; flow cytometry
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