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).

Keywords: ANXA11; Amyotrophic lateral sclerosis; FUS; TDP-43; biological condensates; fronto-temporal dementia; gelation; hydrogels; local RNA translation; neuronal transport granules; phase separation; stress granules.

Figure 1

Genetic overlap between ALS and FTLD. Genetic profiling of familial and sporadic cases of ALS and FTLD have revealed a striking level of overlap between genes linked to each disease. The shared genetic basis for these seemingly distinct clinical syndromes suggests a common core pathophysiology. Most genes linked to either disease cluster into one of three groups: proteostasis and sorting, cytoskeleton and transport, or RNA-binding. Additionally, several genes across these functional groups encode proteins that form biological condensates involved in RNA transport and translation in remote neuronal compartments, strongly linking this biophysical phenomenon to disease pathogenesis.

Figure 2

Biological condensates form free droplets and membrane-associated superstructures. In the dispersed state, protein scaffolds (green circles) and cargo/client RNA molecules (red lines) are intermixed with solute molecules (black circles). Under appropriate conditions, protein scaffolds can phase separate to form a liquid droplet enriched in the scaffold protein and client RNA. Some phase separating proteins, such as A11, can also assemble as 2D- and 3D condensates on membrane surfaces (Edited to correspond to panel labels). A—Monodisperse FUS. B—FUS condensates. C—Annexin A11 enables the attachment of biological condensates to membranes. Liposomes (blue), ANXA11 (red), G3BP1 RNPs (green). D– In the dispersed state, protein scaffolds (green dots) and cargo/client RNA molecules (magenta dots) are intermixed with solute molecules (grey dots). E—Under appropriate conditions, protein scaffolds can phase separate to form liquid droplets enriched in the scaffold protein and client RNA. Owing to their lack of delimiting membranes, these structures can fuse with each other to form larger condensates. F—Some phase separating proteins, such as annexin A11(orange dots), can assemble as 2D and 3D condensates on membranes, enabling the scaffolding of non-lipid-binding condensates.

Figure 3

The roles of proteins forming biological condensates in the transport and local translation of RNAs in remote synaptic compartments in neurons. These proteins form RNP granule scaffolds for binding of RNA and RNA translation machinery, and for the subsequent long-range intracellular transport of these granules to distal neuronal compartments such as dendritic spines and axon terminals (green arrows). Disease associated mutations and pathological posttranslational modification of these proteins result in the formation of irreversible aggregates that sequester RNP granule cargo, and/or failure of intra-neuronal transport of the RNP granules (red arrows).