Abstract
Liquid-liquid phase separation (LLPS) is emerging as a major principle for the mesoscale organization of proteins, RNAs, and membrane-bound organelles into biomolecular condensates. These condensates allow for rapid cellular responses to changes in metabolic activities and signaling. Nowhere is this regulation more important than in neurons and glia, where cellular physiology occurs simultaneously on a range of time- and length-scales. In a number of neurodegenerative diseases, such as Amyotrophic Lateral Sclerosis (ALS), misregulation of biomolecular condensates leads to the formation of insoluble aggregates—a pathological hallmark of both sporadic and familial ALS. Here, we summarize how the emerging knowledge about the LLPS of ALS-related proteins corroborates with their aggregation. Understanding the mechanisms that lead to protein aggregation in ALS and how cells respond to these aggregates promises to open new directions for drug development.
Highlights
Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease caused by the selective death of motor neurons in the spinal cord and brain
RNA-binding proteins (RBPs) play an important role in the regulation of RNA metabolism (Nussbacher et al, 2015, 2019; Xue et al, 2020) and many of them are prone to undergo liquid-liquid phase separation (LLPS) and form fluid condensates (Lin et al, 2015; Mittag and Parker, 2018)
The aberrant phase separation of fused in sarcoma (FUS) leads to the formation of cytosolic aggregates in a concentration-dependent fashion and lysosomes are juxtaposed to these aggregates (Trnka et al, 2021)
Summary
Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease caused by the selective death of motor neurons in the spinal cord and brain. The first identified mutation linked to ALS was in the gene encoding cytoplasmic enzyme superoxide dismutase 1 (SOD1) (Rosen et al, 1993). Over 40 additional genes related to ALS have been discovered with the most common genetic mutation in the chromosome nine open reading frame 72 (C9orf72) gene observed in ~40% of fALS patients (Taylor et al, 2016). A number of ALS-related genes encode RNA-binding proteins (RBPs) including TAR DNA-binding protein 43 (TDP-43), fused in sarcoma (FUS), heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) and T-cell restricted intracellular antigen-1 (TIA-1) (Zhao et al, 2018; Kim et al, 2021). RBPs display tendency to aggregate and their presence is detected in the intracellular cytoplasmic aggregates, the key element in degenerating motor neurons of patients with
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