MOLECULAR MECHANISMS OF TDP-43 MEDIATED NEURODEGENERATION

Abstract

My work shows that: (1) Point mutants remodel propensity of WT TDP-43 C terminal domain to form β-rich oligomers and bind to single-stranded DNAs; (2) Interdomain interactions exist between RRMs and CTD that antagonize pathologic aggregation; (3) TDP-43 NTD can be induced while CTD is significantly enhanced by ssDNA to undergo liquid-liquid phase separation; (4) Adenosine triphosphate (ATP) at physiological concentration can bind to TDP- 43 oligomerization interface and induces formation of solenoid-like structures.