Are aberrant phase transitions a driver of cellular aging?

Abstract

Why do cells age? Recent advances show that the cytoplasm is organized into many membrane-less compartments via a process known as phase separation, which ensures spatiotemporal control over diffusion-limited biochemical reactions. Although phase separation is a powerful mechanism to organize biochemical reactions, it comes with the trade-off that it is extremely sensitive to changes in physical-chemical parameters, such as protein concentration, pH, or cellular energy levels. Here, we highlight recent findings showing that age-related neurodegenerative diseases are linked to aberrant phase transitions in neurons. We discuss how these aberrant phase transitions could be tied to a failure to maintain physiological physical-chemical conditions. We generalize this idea to suggest that the process of cellular aging involves a progressive loss of the organization of phase-separated compartments in the cytoplasm.

Keywords: aging; amyotrophic lateral sclerosis; chaperone; intrinsically disordered protein; mitochondria; neurodegeneration; phase separation; protein aggregation; protein quality control.

Figure 1

Sensitivity of phase separation to changing environmental conditions. A: Phase diagram of a binary mixture as a function of temperature T and concentration c. B and C: Upon decreasing the temperature an initially mixed state of mean concentration c ₀ demixes, often leading to the formation of liquid droplets. D: The concentration of droplets inside minus outside, c _in−c _out, exhibits a jump‐like response when crossing the binodal line in A). Reverting the temperature change or weakly perturbing for example the pH or the salt concentration (dashed line in A and D) can dissolve the drops again.

Figure 2

Dynamic behavior of FUS liquid droplets and droplet aging. A: Recovery of fluorescence intensity of an in vitro formed FUS–GFP droplet after half‐bleach. The site of photobleach is marked by a red arrow. B: Montage of two in vitro reconstituted FUS–GFP droplets fusing under shear flow. C: Aging of in vitro reconstituted liquid droplets into fibrous aggregates.

Figure 3

Continuum model of phase separation by intrinsically disordered proteins. An intrinsically disordered protein (shown in red) undergoes a phase transition into a liquid droplet by liquid–liquid demixing. The droplet “ages” with time and adopts different structures and material properties (gel, solid‐like fibrous aggregates). The images on the top show purified FUS protein forming liquid droplets, a gel, and fibrous aggregates 21. Bottom: The hypothetical proteins A–E span the whole range of the continuum. Pathological forms of these proteins are highlighted in red.