Glutathionylation on RNA-binding proteins: a regulator of liquidliquid phase separation in the pathogenesis of amyotrophic lateral sclerosis

Abstract

RNA-binding proteins (RBPs) containing low-sequence complexity domains mediate the formation of cellular condensates and membrane-less organelles with biological functions via liquidliquid phase separation (LLPS). However, the abnormal phase transition of these proteins induces the formation of insoluble aggregates. Aggregates are pathological hallmarks of neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS). The molecular mechanisms underlying aggregate formation by ALS-associated RPBs remain largely unknown. This review highlights emerging studies on various posttranslational modifications (PTMs) related to protein aggregation. We begin with the introduction of several ALS-associated RBPs that form aggregates induced by phase separation. In addition, we highlight our recent discovery of a new PTM involved in the phase transition during the pathogenesis of fused-in-sarcoma (FUS)-associated ALS. We suggest a molecular mechanism through which LLPS mediates glutathionylation in FUS-linked ALS. This review aims to provide a detailed overview of the key molecular mechanisms of LLPS-mediated aggregate formation by PTMs, which will help further the understanding of the pathogenesis and development of ALS therapeutics. Brain disease: Understanding protein aggregation in amyotrophic lateral sclerosis The addition of peptide tags to proteins implicated in neurodegeneration can alter the ways in which disease-causing aggregates form inside brain cells. Kiyoung Kim and colleagues from Soonchunhyang University, Asan, South Korea, review how molecular changes made to RNA-binding proteins associated with amyotrophic lateral sclerosis (ALS) can affect the dynamics by which these proteins assemble inside liquid-like compartments within the cell. One such change, known as glutathionylation, involves the addition of antioxidant peptide tags to proteins such as the RNA-binding protein FUS, a key driver of ALS onset and progression. This process alters the electrical charge of FUS, changing the way it interacts with other proteins, and reducing its propensity to form disease-promoting aggregates. A better understanding of this process could aid in the treatment and management of ALS and related brain diseases.