In fact, well known ALS-related mutations, such as substitutions in the mostly disordered C-terminus of TDP-43 and the hexanucleotide expansion in C9orf72, were shown to impair phase separation of these proteins, suggesting their relevance in the onset of the pathological condition [86,87]. Additionally, altered proteostasis, which leads to the formation of aggregates in neuronal cells, is a hallmark of such conditions and was related to phase separation. Nonetheless, a complete understanding of how this aggregation influences the pathological outcome is still missing and requires further investigation to elucidate the exact relationship linking the fiber formation and the toxic effect
Further evidence for this mechanism of pathogenesis has come from studying amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Work by several groups indicates that disease-related proteins, including FUS,, hnRNPA1, and TDP43, form liquid droplets before aggregating into pathological clumps. Genetic mutations found in patients with more aggressive forms of ALS or FTD increase the speed with which droplets of purified FUS, hnRNPA1, and TDP43 morph into plaque-like tangles. There is now a concerted effort to identify ways of preventing these proteins from undergoing pathological phase separation in cells, and even reversing the process after it has occurred.
THIS PAPER IS REALLY GOOD Physiological, pathological, and targetable membraneless organelles in neurons
The cell has various molecular chaperones that remodel misfolded proteins and contribute to proper maintenance of RNP-granule dynamics (
). Nuclear-import receptors also act as chaperones and dissolvases that reverse LLPS and aberrant phase separation of their RBP cargo (
,
,
,
). Small-molecule enhancers of these chaperones or de novo–designed chaperone proteins with enhanced disaggregase activity thus present promising approaches for targeting neurodegenerative diseases (
,
,
,
).