Abstract
TAR DNA binding protein (TDP-43) is a nucleic acid binding protein associated with insoluble cytoplasmic aggregates in several neurodegenerative disorders, including 97% of the ALS cases. In healthy individuals, TDP-43 is primarily localized to the nucleus; it can shuttle between the nucleus and the cytoplasm, and is involved in several aspects of RNA processing including transcription, splicing, RNA stability, transport, localization, stress granule (SG) formation, and translation. Upon stress, TDP-43 aggregates in the cytoplasm and associates with several types of RNA and protein assemblies, resulting in nuclear depletion of TDP-43. Under conditions of prolonged stress, cytoplasmic TDP-43 undergoes liquid-liquid phase separation (LLPS) and becomes less mobile. Evidence exists to support a scenario in which insoluble TDP-43 complexes sequester RNA and/or proteins causing disturbances in both ribostasis and proteostasis, which in turn contribute to neurodegeneration. However, the relationship between RNA binding and TDP-43 toxicity remains unclear. Recent studies provide conflicting views on the role of RNA in TDP-43 toxicity, with some finding RNA as a toxic factor whereby RNA binding contributes to TDP-43 toxicity, while others find RNA to be a protective factor that inhibits TDP-43 aggregation. Here we review and discuss these recent reports, which ultimately highlight the importance of understanding the heterogeneity of TDP-43 assemblies and collectively point to solubilizing TDP-43 as a potential therapeutic strategy.
Highlights
Deficiencies in several dozen genes have been associated with ALS (Peters et al, 2015), a great proportion of patients have no known ALS associated mutation and disease etiology remains poorly understood
Since its discovery in 2006 as a major component of pathological aggregates, we have learned a great deal about the involvement of TDP-43 in several steps of RNA processing including transcription, splicing, RNA stability, transport, localization, and translation, with several excellent reviews being recently written on the role of TDP-43 in these processes (Bowden and Dormann, 2016; Coyne et al, 2017b; Butti and Patten, 2018; Lehmkuhl and Zarnescu, 2018; Afroz et al, 2019; Birsa et al, 2019; Hergesheimer et al, 2019); its precise involvement in disease remains to be elucidated
Several recent publications demonstrate that phosphoTDP-43 containing pathological aggregates can form and persist independently of stress granule (SG), the evolution of toxic TDP-43 complexes from SGs remains a strong possibility supported by some of the same studies and many others
Summary
Deficiencies in several dozen genes have been associated with ALS (Peters et al, 2015), a great proportion of patients have no known ALS associated mutation and disease etiology remains poorly understood. Perhaps due to stress caused by aging, the presence of mutations or environmental insults, cytoplasmic TDP-43 complexes could become insoluble and trap RNA and/or proteins causing disturbances in both ribostasis and proteostasis, followed by motor neuron dysfunction and death Supporting this hypothesis, a number of studies have shown that when overexpressed, TDP-43 alters the transport, localization, and translation of specific mRNAs in both axons and dendrites (Wang et al, 2008; Fallini et al, 2012; Majumder et al, 2012, 2016; Alami et al, 2014; Coyne et al, 2014, 2017a; Liu-Yesucevitz et al, 2014). The presence of these otherwise functional aggregates provides an opportunity for seeding and formation of muscle pathological aggregates that have been observed in disease (Vogler et al, 2018)
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