Role and therapeutic potential of liquid–liquid phase separation in amyotrophic lateral sclerosis

• Published in: Journal of molecular cell biology 2021-04, Vol.13 (1), p.15-28
• Main Authors: Pakravan, Donya, Orlando, Gabriele, Bercier, Valérie, Van Den Bosch, Ludo
• Format: Article
• Language: English
• Subjects: Amyotrophic Lateral Sclerosis - drug therapy; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - pathology; Autophagy - drug effects; DNA-Binding Proteins - antagonists & inhibitors; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Humans; Intrinsically Disordered Proteins - antagonists & inhibitors; Intrinsically Disordered Proteins - genetics; Intrinsically Disordered Proteins - metabolism; Molecular Chaperones - pharmacology; Molecular Chaperones - therapeutic use; Mutation; Oligonucleotides, Antisense - pharmacology; Oligonucleotides, Antisense - therapeutic use; Protein Aggregation, Pathological - drug therapy; Protein Aggregation, Pathological - genetics; Protein Aggregation, Pathological - pathology; Protein Folding - drug effects; Reviews; RNA-Binding Protein FUS - antagonists & inhibitors; RNA-Binding Protein FUS - genetics; RNA-Binding Protein FUS - metabolism
• ISSN: 1759-4685; 1674-2788; 1759-4685
• DOI: 10.1093/jmcb/mjaa049

Abstract Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disease selectively affecting motor neurons, leading to progressive paralysis. Although most cases are sporadic, ∼10% are familial. Similar proteins are found in aggregates in sporadic and familial ALS, and over the last decade, research has been focused on the underlying nature of this common pathology. Notably, TDP-43 inclusions are found in almost all ALS patients, while FUS inclusions have been reported in some familial ALS patients. Both TDP-43 and FUS possess ‘low-complexity domains’ (LCDs) and are considered as ‘intrinsically disordered proteins’, which form liquid droplets in vitro due to the weak interactions caused by the LCDs. Dysfunctional ‘liquid–liquid phase separation’ (LLPS) emerged as a new mechanism linking ALS-related proteins to pathogenesis. Here, we review the current state of knowledge on ALS-related gene products associated with a proteinopathy and discuss their status as LLPS proteins. In addition, we highlight the therapeutic potential of targeting LLPS for treating ALS.