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

ABSTRACTFailure in protein quality control can often lead to protein aggregation, yet in neuro-degenerative diseases, by the time aggregates can be seen, the cells have advanced well into the disease pathology. Here, we develop a quantitative imaging approach to study the protein aggregation process in living mammalian cells with unprecedented spatio-temporal resolution. We find that sub-diffractive precursor aggregates may form even in untreated cells, and their size distribution is exactly as predicted for a system undergoing a first order phase transition. Practically, this implies that as soon as aggregates reach a critical size (Rc = 162 ± 4 nm untreated cells), they will spontaneously grow into large inclusions. Our data suggest that a previously uncharacterized, RuvBL1 dependent mechanism clears aggregates above the critical size. Our study unveils the existence of sub-diffractive aggregates in living cells; and the strong agreement between cellular data and a nucleation theory, based on first order phase transition, provides insight into regulatory steps in the early stages of aggregate formation in vivo.

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

eLife ◽

10.7554/elife.39695 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 24

Author(s):

Arjun Narayanan ◽

Anatoli Meriin ◽

J Owen Andrews ◽

Jan-Hendrik Spille ◽

Michael Y Sherman ◽

...

Keyword(s):

Phase Transition ◽

Order Phase Transition ◽

Mammalian Cells ◽

Normal Growth ◽

Editorial Note ◽

Lag Phase ◽

First Order ◽

Transition Mechanism ◽

First Order Phase Transition ◽

First Order Phase

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.Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (<xref ref-type="decision-letter" rid="SA1">see decision letter</xref>).

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Surface ordering and destruction of the first order phase transition smectic A-smectic C* in free standing smectic films

Journal de Physique II ◽

10.1051/jp2:1994237 ◽

1994 ◽

Vol 4 (10) ◽

pp. 1865-1874 ◽

Cited By ~ 10

Author(s):

E. Demikhov ◽

U. Hoffmann ◽

H. Stegemeyer

Keyword(s):

Phase Transition ◽

Order Phase Transition ◽

Free Standing ◽

First Order ◽

Surface Ordering ◽

Smectic A ◽

Smectic C ◽

First Order Phase Transition ◽

First Order Phase

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Gravitational wave signals of dark matter freeze-out

Journal of High Energy Physics ◽

10.1007/jhep02(2021)022 ◽

2021 ◽

Vol 2021 (2) ◽

Cited By ~ 3

Author(s):

Danny Marfatia ◽

Po-Yan Tseng

Keyword(s):

Phase Transition ◽

Dark Matter ◽

Gravitational Waves ◽

Order Phase Transition ◽

First Order ◽

Stochastic Background ◽

First Order Phase Transition ◽

Relic Abundance ◽

First Order Phase ◽

Freeze Out

Abstract We study the stochastic background of gravitational waves which accompany the sudden freeze-out of dark matter triggered by a cosmological first order phase transition that endows dark matter with mass. We consider models that produce the measured dark matter relic abundance via (1) bubble filtering, and (2) inflation and reheating, and show that gravitational waves from these mechanisms are detectable at future interferometers.

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