Biomolecular condensates in neurodegeneration and cancer

Abstract

The intracellular environment is partitioned into functionally distinct compartments containing specific sets of molecules and reactions. Biomolecular condensates, also referred to as membrane‐less organelles, are diverse and abundant cellular compartments that lack membranous enclosures. Molecules assemble into condensates by phase separation; multivalent weak interactions drive molecules to separate from their surroundings and concentrate in discrete locations. Biomolecular condensates exist in all eukaryotes and in some prokaryotes, and participate in various essential house‐keeping, stress‐response and cell type‐specific processes. An increasing number of recent studies link abnormal condensate formation, composition and material properties to a number of disease states. In this review, we discuss current knowledge and models describing the regulation of condensates and how they become dysregulated in neurodegeneration and cancer. Further research on the regulation of biomolecular phase separation will help us to better understand their role in cell physiology and disease.

Protein phase separation and its role in tumorigenesis

“…This hardening of FUS condensates is associated with the formation of supramolecular FUS fibrils that have properties of amyloid-like aggregates. Besides neurodegenerative disorders, current research further suggests emerging roles of aberrant condensates in cancer ( Alberti and Dormann, 2019 ; Spannl et al, 2019 ).…”

Sequestration of TDP-43216-414aggregates by cytoplasmic expression of the proSAAS chaperone

“…A literature search to identify protein condensates similar to proSAAS spheres revealed that most aggresomes described to date are nuclear, much smaller (less than one micron), and heterogeneously shaped rather than spherical (reviewed in (Spannl et al, 2019;Wolozin and Ivanov, 2019)). Three nuclear protein condensates do produce membrane-less spherical particles.…”

Membraneless organelles in cell biology

“…While membraneless compartments have important functions in cell (neurons) physiology, they can become pathological when formed on the expression of mutated proteins and/or when cells are exposed to stress. The same review describes how this can lead to abnormal aggregation of granule components, as is observed in pathological contexts, and is thought to underlie the progression of neurodegenerative diseases . Interestingly, aberrant phase separation also seems to occur in cancer as reported in the review from Spannl et al…”

“…The same review describes how this can lead to abnormal aggregation of granule components, as is observed in pathological contexts, and is thought to underlie the progression of neurodegenerative diseases . Interestingly, aberrant phase separation also seems to occur in cancer as reported in the review from Spannl et al…”