title: Disease causing mutants of TDP-43 nucleic acid binding domains are resistant to aggregation and have increased stability and half-life.
abstract: Over the last two decades many secrets of the age-related human neural proteinopathies have been revealed. A common feature of these diseases is abnormal, and possibly pathogenic, aggregation of specific proteins in the effected tissue often resulting from inherent or decreased structural stability. An archetype example of this is superoxide dismutase-1, the first genetic factor to be linked with amyotrophic lateral sclerosis (ALS). Mutant or posttranslationally modified TAR DNA binding protein-32 (TDP-43) is also strongly associated with ALS and an increasingly large number of other neurodegenerative diseases, including frontotemporal lobar degeneration (FTLD). Cytoplasmic mislocalization and elevated half-life is a characteristic of mutant TDP-43. Furthermore, patient age at the onset of disease symptoms shows a good inverse correlation with mutant TDP-43 half-life. Here we show that ALS and FTLD-associated TDP-43 mutations in the central nucleic acid binding domains lead to elevated half-life and this is commensurate with increased thermal stability and inhibition of aggregation. It is achieved without impact on secondary, tertiary, or quaternary structure. We propose that tighter structural cohesion contributes to reduced protein turnover, increasingly abnormal proteostasis and, ultimately, faster onset of disease symptoms. These results contrast our perception of neurodegenerative diseases as misfolded proteinopathies and delineate a novel path from the molecular characteristics of mutant TDP-43 to aberrant cellular effects and patient phenotype.
authors.affiliation: Molecular Biophysics Group, Institute of Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Liverpool L69 7ZB, United Kingdom.
authors.forename: James A
authors.initials: JA
authors.lastname: Austin
authors.forename: Gareth S A
authors.initials: GS
authors.lastname: Wright
authors.forename: Seiji
authors.initials: S
authors.lastname: Watanabe
authors.forename: J Günter
authors.initials: JG
authors.lastname: Grossmann
authors.forename: Svetlana V
authors.initials: SV
authors.lastname: Antonyuk
authors.forename: Koji
authors.initials: K
authors.lastname: Yamanaka
authors.forename: S Samar
authors.initials: SS
authors.lastname: Hasnain
mesh_terms: D004268:DNA-Binding Proteins / Q000235:genetics*; D005453:Fluorescence; D006207:Half-Life; D006801:Humans; D009154:Mutation / Q000235:genetics; D019636:Neurodegenerative Diseases / Q000453:epidemiology* / Q000235:genetics* / Q000503:physiopathology; D055550:Protein Stability; D053838:Scattering, Small Angle
chemical_list: D004268:DNA-Binding Proteins
keywords: SAXS; motor neuron disease; oligemisation; protein degradation