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

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’ (IDPs), 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.

A Deletion of the Nuclear Localization Signal Domain in the Fus Protein Induces Stable Post-stress Cytoplasmic Inclusions in SH-SY5Y Cells

“…In pathological conditions, like the neurodegenerative process in ALS, the disassembling process might become impaired ( Buratti and Barrale, 2010 ; Li et al, 2013 ; Fernandes et al, 2018 ). This process most probably occurs because of a higher protein density in the granules, with a consequent liquid-to-solid phase change of SGs, exceedingly facilitated by ALS-related proteins with a prion-like low-complexity domain, like TDP-43, Ataxin-1, Ataxin-2 and FUS ( Li et al, 2013 ; Pakravan et al, 2021 ). In particular, the RNP FUS is a critical component of SGs after stress ( Dormann et al, 2010 ; Lo Bello et al, 2017 ).…”

“…The resulting elevated cytoplasmic FUS protein levels in cells with the P525L mutation or with the NLS deletion represent the basis for its strong propensity to enter into SGs massively, thus possibly facilitating the formation of permanent, SGs–derived, cytoplasmic inclusions ( Ederle and Dormann, 2017 ; Dudman and Qi, 2020 ; Pakravan et al, 2021 ). FUS-containing inclusions have been observed in sporadic and familial ALS ( Deng et al, 2010 ; Tyzack et al, 2019 ) and mice overexpressing the wild type protein ( Mitchell et al, 2013 ).…”

Altered Phase Separation and Cellular Impact in C9orf72-Linked ALS/FTD

“…Again, post-translational modifications can be targeted. As detailed above symmetric dimethylation of poly-GR reduces its propensity for LLPS and appears to be protective (Gittings et al, 2020;Pakravan et al, 2020). The enzymes responsible for arginine methylation belong to the protein arginine methyltransferase (PRMT) family (Yang and Bedford, 2013).…”

Potential Therapeutic Role of HDAC Inhibitors in FUS-ALS

“…Post-translational modifications strategies for ALS are hypothesized to be a potential therapeutic targets (Pakravan et al, 2020 ). Acetylation of the RRM domain could be a valid therapeutic strategy ( Figure 2 ).…”