[Conjoint pathological cascades mediated by RNA-binding proteins, TDP-43, FUS and ataxin-2]

Recently, critical RNA-binding proteins that are directly associated with the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) have also been identified, including TAR DNA-binding protein (TDP-43), fused in sarcoma/translated in liposarcoma (FUS) protein and ataxin-2. TDP-43 and FUS are normally localized in the nucleus, in sites affected by ALS and FTLD-U, but both are mislocalized to the cytoplasm and form cytoplasmic inclusions. They are transported to the nucleus via nuclear import receptors, but also contribute to the formation of stress granules (SGs), which are intracytoplasmic structures incorporating RNA. C-terminal truncations of TDP-43 eliminate the nuclear transport signal and cause mislocalization of the protein to the cytoplasm, where it accumulates and forms SGs. ALS-associated FUS mutations impair nuclear transport and cause mislocalization of FUS to the cytoplasm, where it also contributes to assembly of SGs. Furthermore, the ALS susceptibility factor ataxin-2 is recently identified as a potent modifier of TDP-43 toxicity and growing evidence indicates that intermediate-length polyglutamine expansions in ataxin-2 are a genetic risk factor for ALS. Interestingly, ataxin-2 is also a cytoplasmic RNA-binding protein and a constituent protein of SGs, suggesting that it is a part of the common pathological cascade formed by TDP-43, FUS and ataxin-2. Thus, we propose that aberrant distribution of the RNA-binding proteins TDP-43, FUS, and ataxin-2 into the cytoplasm leads to impairment of the RNA quality control system, forming the core of the ALS/FTLD-U degenerative cascade.