title: Biology and Pathobiology of TDP-43 and Emergent Therapeutic Strategies.
abstract: Cytoplasmic TDP-43 mislocalization and aggregation is a pathological hallmark of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. TDP-43 is an RNA-binding protein (RBP) with a prion-like domain (PrLD) that promotes TDP-43 misfolding. PrLDs possess compositional similarity to canonical prion domains of various yeast proteins, including Sup35. Strikingly, disease-causing TDP-43 mutations reside almost exclusively in the PrLD and can enhance TDP-43 misfolding and toxicity. Another ∼70 human RBPs harbor PrLDs, including FUS, TAF15, EWSR1, hnRNPA1, and hnRNPA2, which have surfaced in the etiology of neurodegenerative diseases. Importantly, PrLDs enable RBP function and mediate phase transitions that partition functional ribonucleoprotein compartments. This PrLD activity, however, renders RBPs prone to populating deleterious oligomers or self-templating fibrils that might spread disease, and disease-linked PrLD mutations can exacerbate this risk. Several strategies have emerged to counter TDP-43 proteinopathies, including engineering enhanced protein disaggregases based on Hsp104.
authors.affiliation: Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Lin
authors.initials: L
authors.lastname: Guo
authors.affiliation: Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: James
authors.initials: J
authors.lastname: Shorter
mesh_terms: D004268:DNA-Binding Proteins / Q000235:genetics*; D006801:Humans; D009154:Mutation; D016601:RNA-Binding Proteins / Q000235:genetics*; D057177:TDP-43 Proteinopathies / Q000235:genetics* / Q000473:pathology
chemical_list: D004268:DNA-Binding Proteins; D016601:RNA-Binding Proteins; C000598624:TARDBP protein, human