Special LMNN Seminar- RNA-binding proteins in neurodegeneration – from nuclear transport defects to aberrant phase transitions

Pathological protein aggregates are a central hallmark of all neurodegenerative diseases. In the related disorders ALS (amyotrophic lateral sclerosis) and FTD (frontotemporal dementia), the pathological aggregates consist mostly of the ubiquitous RNA-binding proteins TDP-43 or FUS. Both proteins are usually located in the nucleus, whereas in neurons and glial cells of ALS/FTD patients, they are partially lost from the nucleus and accumulate in large cytoplasmic inclusions. Which molecular defects cause TDP-43 or FUS mislocalization and aggregation in ALS/FTD patients and how we can possibly prevent or revert them are central questions that we try to address in my lab.
For FUS, we have successfully used cellular and in vitro models combined with neuropathological analysis of human post-mortem brains to identify key pathomechanisms that cause FUS mislocalization and aggregation in ALS and FTD patients: In ALS-FUS, genetic mutations in the nuclear localization signal (NLS) of FUS cause impaired binding to the nuclear import receptor Transportin. This defect impairs nuclear import of FUS and, upon cellular stress, favors recruitment of FUS into stress granules, where FUS aggregation may be promoted due to high local FUS concentrations. In FTD-FUS patients, Transportin is aggregated and a post-translational modification of FUS, arginine methylation, is lost. Recently, we have shown that both Transportin and arginine methylation keep FUS soluble in the cytoplasm and prevent aberrant liquid-to-solid state transition and accumulation of FUS in stress granules. Our work suggests that certain binding proteins and post-translational modifications can modulate aberrant solidification of ALS/FTD-linked RNA-binding proteins and hence could potentially be targeted in new therapeutic approaches.