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Disease causing mutants of TDP-43 nucleic acid binding domains are resistant to aggregation and have increased stability and half-life

DOI: 10.1073/pnas.1317317111 DOI Help

Authors: James A. Austin (University of Liverpool) , Gareth S. A. Wright (University of Liverpool) , Seiji Watanabe (Nagoya University) , J. G√ľnter Grossmann (University of Liverpool) , Svetlana V. Antonyuk (University of Liverpool) , Koji Yamanaka (Nagoya University) , S. Samar Hasnain (University of Liverpool)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Proceedings Of The National Academy Of Sciences , VOL 111 , PAGES 4309 - 4314

State: Published (Approved)
Published: March 2014
Diamond Proposal Number(s): 9218

Open Access Open Access

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.

Journal Keywords: motor neuron disease; oligemisation; SAXS; protein degradation

Subject Areas: Medicine, Chemistry, Biology and Bio-materials

Instruments: B23-Circular Dichroism

Other Facilities: Soleil DISCO beamline

Added On: 20/10/2017 11:38

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