A first order phase transition mechanism underlies protein aggregation in mammalian cells

Arjun Narayanan, Anatoli Meriin, J. Owen Andrews, Jan Hendrik Spille, Michael Y. Sherman, Ibrahim I. Cisse

Research output: Contribution to journalArticlepeer-review

Abstract

The formation of misfolded protein aggregates is a hallmark of neurodegenerative diseases. The aggregate formation process exhibits an initial lag phase when precursor clusters spontaneously assemble. However, most experimental assays are blind to this lag phase. We develop a quantitative assay based on super-resolution imaging in fixed cells and light sheet imaging of living cells to study the early steps of aggregation in mammalian cells. We find that even under normal growth conditions mammalian cells have precursor clusters. The cluster size distribution is precisely that expected for a so-called super-saturated system in first order phase transition. This means there exists a nucleation barrier, and a critical size above which clusters grow and mature. Homeostasis is maintained through a Szilard model entailing the preferential clearance of super-critical clusters. We uncover a role for a putative chaperone (RuvBL) in this disassembly of large clusters. The results indicate early aggregates behave like condensates.

Original languageEnglish (US)
Article numbere39695
JournaleLife
Volume8
DOIs
StatePublished - Feb 2019

ASJC Scopus subject areas

  • General Neuroscience
  • General Biochemistry, Genetics and Molecular Biology
  • General Immunology and Microbiology

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