AUTHOR=Mompeán Miguel , Baralle Marco , Buratti Emanuele , Laurents Douglas V. TITLE=An Amyloid-Like Pathological Conformation of TDP-43 Is Stabilized by Hypercooperative Hydrogen Bonds JOURNAL=Frontiers in Molecular Neuroscience VOLUME=9 YEAR=2016 URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2016.00125 DOI=10.3389/fnmol.2016.00125 ISSN=1662-5099 ABSTRACT=
TDP-43 is an essential RNA-binding protein forming aggregates in almost all cases of sporadic amyotrophic lateral sclerosis (ALS) and many cases of frontotemporal lobar dementia (FTLD) and other neurodegenerative diseases. TDP-43 consists of a folded N-terminal domain with a singular structure, two RRM RNA-binding domains, and a long disordered C-terminal region which plays roles in functional RNA regulatory assemblies as well as pernicious aggregation. Evidence from pathological mutations and seeding experiments strongly suggest that TDP-43 aggregates are pathologically relevant through toxic gain-of-harmful-function and/or harmful loss-of-native-function mechanisms. Recent, but not early, microscopy studies and the ability of TDP-43 aggregates to resist harsh treatment and to seed new pathological aggregates