Inherited and Sporadic Amyotrophic Lateral Sclerosis and Fronto-Temporal Lobar Degenerations arising from Pathological Condensates of Phase Separating Proteins

Abstract

Recent work on the biophysics of proteins with low complexity, intrinsically disordered domains that have the capacity to form biological condensates has profoundly altered the concepts about the pathogenesis of inherited and sporadic neurodegenerative disorders associated with pathological accumulation of these proteins. In the present review, we use the FUS, TDP-43 and A11 proteins as examples to illustrate how missense mutations and aberrant post-translational modifications of these proteins cause amyotrophic lateral sclerosis (ALS) and fronto-temporal lobar degeneration (FTLD).

Post-translational Control of RNA-Binding Proteins and Disease-Related Dysregulation

“…Similarly, lysine acetylation of FUS in its nuclear localization signal (NLS) restricts its cellular distribution to the cytoplasm, whereas the same PTM in its RRM disrupts its association with RNA ( Arenas et al, 2020 ). Moreover, PTMs at low-complexity IDRs (e.g., arginine methylation of RGG regions) of some phase-separating RBPs such as FUS strongly influence the formation and characteristics of condensates ( Hofweber et al, 2018 ; Qamar et al, 2018 ; Hofweber and Dormann, 2019 ), including the irreversible transition into hardened aggregates ( Bowden and Dormann, 2016 ; St George-Hyslop et al, 2018 ; Fernandopulle et al, 2019 ; Xue et al, 2020 ).…”

“…The irreversible solidification experienced by condensates is often associated with key mutations in RBP-encoding genes. However, the ability of both wild-type and mutant RBPs to undergo LLPS and gelation can be profoundly altered by PTMs ( Bowden and Dormann, 2016 ; St George-Hyslop et al, 2018 ; Fernandopulle et al, 2019 ; Xue et al, 2020 ). For example, aberrant hyper-phosphorylation, ubiquitylation, acetylation, cysteine oxidation and caspase cleavage of TDP-43 have been related to a pathogenic behavior of this RBP in FTLD and/or ALS, including loss of physiological function, mislocalization and higher aggregation ( Buratti, 2018 ; François-Moutal et al, 2019 ; Prasad et al, 2019 ).…”

“…MLOs play an essential role in the cell by enabling the controlled and selective concentration of particular RBPs, among other biomolecules, to carry out critical biochemical reactions under optimal conditions, separated from the rest of their environment ( Drino and Schaefer, 2018 ; Strom and Brangwynne, 2019 ). However, dysregulation of phase-separating RBPs such as FUS and TAR DNA-binding protein of 43 KDa (TDP-43) can lead to irreversible and aberrant condensate formation, a process deleterious to cells and frequently associated with neurodegenerative diseases, as discussed below ( Bowden and Dormann, 2016 ; St George-Hyslop et al, 2018 ; Fernandopulle et al, 2019 ; Xue et al, 2020 ).…”

Structure of the ALS Mutation Target Annexin A11 Reveals a Stabilising N-Terminal Segment

“…Expression levels of AnxA11 have been linked to various cancers [25][26][27][28][29][30]. Recent studies have revealed that mutations in AnxA11 play an important role in the development of the neurodegenerative disease amyotrophic lateral sclerosis (ALS) [8,[31][32][33][34][35][36][37]. The molecular basis of these mutations is unclear, as an experimentally determined 3D structure of AnxA11 has been lacking.…”

Table_1.pdf

“…MLOs play an essential role in the cell by enabling the controlled and selective concentration of particular RBPs, among other biomolecules, to carry out critical biochemical reactions under optimal conditions, separated from the rest of their environment (Drino and Schaefer, 2018;Strom and Brangwynne, 2019). However, dysregulation of phase-separating RBPs such as FUS and TAR DNA-binding protein of 43 KDa (TDP-43) can lead to irreversible and aberrant condensate formation, a process deleterious to cells and frequently associated with neurodegenerative diseases, as discussed below (Bowden and Dormann, 2016;St George-Hyslop et al, 2018;Fernandopulle et al, 2019;Xue et al, 2020).…”