"STRESSED OUT": The role of FUS and TDP-43 in amyotrophic lateral sclerosis. (September 2020)

• Record Type: Journal Article
• Authors: Aksoy, Yagiz Alp; Deng, Wei; Stoddart, Jack; Chung, Roger; Guillemin, Gilles; Cole, Nicholas James; Neely, Graham Gregory; Hesselson, Daniel
• Is Part Of: International journal of biochemistry & cell biology. Volume 126(2020)
• Publication Date: 2020-09
• Subjects: 3'UTR 3'untranslated region -- ALS Amyotrophic Lateral Sclerosis -- ER endoplasmic reticulum -- FALS familial ALS -- FTLD frontotemporal lobar degeneration -- FUS fused-in-farcoma -- hnRNP heterogeneous nuclear ribonucleoprotein -- NES nuclear export signal -- NLS nuclear localisation signal -- QGSY Gln-Gly-Ser-Tyr -- RGG Arg-Gly-Gly repeat regions -- RRM RNA-recognition motif -- SALS sporadic ALS -- SGs stress granules -- SMN survival of motor neuron protein -- SOD1 superoxide dismutase 1 -- TDP-43, TARDBP TAR DNA-binding protein-43 -- UPR unfolded protein response -- UPS ubiquitin proteasome system -- ZnF zinc-finger motif; FUS -- TDP-43 -- Cellular stress -- Proteinopathy; Biochemistry -- Periodicals; Cytology -- Periodicals; Biochemistry -- Periodicals; Cell Biology -- Periodicals; Biochimie -- Périodiques; Cytologie -- Périodiques; Biochimie; Cytologie; Biochemistry; Cytology; Ressource Internet (Descripteur de forme); Périodique électronique (Descripteur de forme); Periodicals; 572.05
• DOI: 10.1016/j.biocel.2020.105821
• Languages: English
• ISSNs: 1357-2725

Abstract

Abstract: Mutations in fused-in-sarcoma (FUS) and TAR DNA binding protein-43 (TDP-43; TARDBP) are known to cause the severe adult-onset neurodegenerative disorder amyotrophic lateral sclerosis (ALS). Proteinopathy caused by cellular stresses such as endoplasmic reticulum (ER) stress, oxidative stress, mitochondrial stress and proteasomal stress and the formation of stress granules (SGs), cytoplasmic aggregates and inclusions is a hallmark of ALS. FUS and TDP-43, which are DNA/RNA binding proteins that regulate transcription, RNA homeostasis and protein translation are implicated in ALS proteinopathy. Disease-causing mutations in FUS and TDP-43 cause sequestration of these proteins and their interacting partners in the cytoplasm, which leads to aggregation. This mislocalization and formation of aggregates and SGs is cytotoxic and a contributor to neuronal death. We explore how loss-of-nuclear-function and gain-of-cytoplasmic function mechanisms that affect FUS and TPD-43 localization can generate a 'stressed out' neuronal pathology and proteinopathy that drives ALS progression.