Beyond aggregation: Pathological phase transitions in neurodegenerative disease

Abstract

Over the past decade, phase transitions have emerged as a fundamental mechanism of cellular organization. In parallel, a wealth of evidence has accrued indicating that aberrations in phase transitions are early events in the pathogenesis of several neurodegenerative diseases. We review the key evidence of defects at multiple levels, from phase transition of individual proteins to the dynamic behavior of complex, multicomponent condensates in neurodegeneration. We also highlight two concepts, dynamical arrest and heterotypic buffering, that are key to understanding how pathological phase transitions relate to pleiotropic defects in cellular functions and the accrual of proteinaceous deposits at end-stage disease. These insights not only illuminate disease etiology but also are likely to guide the development of therapeutic interventions to restore homeostasis.

Fig. 1.. Two non-exclusive routes lead to fibril formation in neurodegenerative diseases.

Fibril formation may be initiated by a primary and secondary nucleation in dilute solution with subsequent growth through templating additional units. Alternatively, fibril formation may occur via liquid-to-solid phase transition within the dense liquid phase. In the condensed liquid state, fibril formation is facilitated by concentrating proteins and bringing them closer to the threshold for liquid-to-solid phase transition. These routes are not mutually exclusive and may be influenced by context.

Fig. 2.. Condensates arise through a network of heterotypic and homotypic interactions.

Condensates form through phase separation of multiple types of macromolecules. In RNP granules, for example, multivalent proteins and RNA molecules participate in a network of homotypic and heterotypic interactions that collectively determine the concentration threshold for LLPS and the material properties of the resulting condensate. The material properties of biomolecular condensates, such as viscosity, elasticity, and surface tension of the dense phase are governed by the extent of physical crosslinking and the timescales for making and breaking crosslinks within condensates. These material properties influence the spatial organization and diffusion of macromolecules within the dense phase, as well as selective permeability to molecules entering the condensate. These material properties are tightly regulated and directly linked to condensate function.

Fig. 3.. Disruption of the physiologically relevant interplay between homotypic and heterotypic interaction can lead to pathological phase transitions.

Within multicomponent condensates, homotypic interactions are typically buffered by an abundance of heterotypic interactions. This buffering guards against pathological homotypic interactions that may give rise to liquid-to-solid phase transition and fibril formation. In this simplified example, two types of macromolecules are illustrated, each depicted with two interacting domains (rectangles) connected by a spacer region (black line). Purple macromolecules can form homotypic interactions with other purple macromolecules or heterotypic interactions with blue macromolecules. Blue macromolecules can form heterotypic interactions with purple macromolecules. Under normal conditions (left), the concentration of blue macromolecules is such that heterotypic interactions buffer any homotypic interactions. Four scenarios are shown in which this buffering is disrupted: (1–2) imbalances in the relative concentrations of condensate constituents, (3) competition for heterotypic interactions by the presence of an additional molecule, and (4) pathological mutations that favor homotypic interactions. In each case, excessive homotypic interactions can lead to the deposition of solid-like structures within condensates if they escape protein quality control mechanisms.