TDP-43 interacts with amyloid-ß, inhibits fibrillization, and worsens pathology in a model of Alzheimer's disease.

TDP-43 inclusions are found in many Alzheimer's disease (AD) patients presenting faster disease progression and greater brain atrophy. Previously, we showed full-length TDP-43 forms spherical oligomers and perturbs amyloid-ß (Aß) fibrillization. To elucidate the role of TDP-43 in AD, here, we examined the effect of TDP-43 in Aß aggregation and the attributed toxicity in mouse models. We found TDP-43 inhibited Aß fibrillization at initial and oligomeric stages. Aß fibrillization was delayed specifically in the presence of N-terminal domain containing TDP-43 variants, while C-terminal TDP-43 was not essential for Aß interaction. TDP-43 significantly enhanced Aß's ability to impair long-term potentiation and, upon intrahippocampal injection, caused spatial memory deficit. Following injection to AD transgenic mice, TDP-43 induced inflammation, interacted with Aß, and exacerbated AD-like pathology. TDP-43 oligomers mostly colocalized with intracellular Aß in the brain of AD patients. We conclude that TDP-43 inhibits Aß fibrillization through its interaction with Aß and exacerbates AD pathology.

Structural insights into the duplex DNA processing of TREX2.

The three prime repair exonuclease 2 (TREX2) is an essential 3'-to-5' exonuclease that functions in cell proliferation, genome integrity and skin homeostasis maintenance. The abnormal expression level of TREX2 can result in broken chromosome, increased susceptibility to skin carcinogenesis and Psoriasis. However, the molecular mechanisms of how TREX2 binds and processes its natural substrates, dsDNA or chromosomal DNA, to maintain genome stability remain unclear. In this study, we present four new crystal structures: apo-TREX2, TREX2 in complex with two different dsDNA substrates, and TREX2 in complex with a processed dsDNA product. Analysis of the structures reveals that TREX2 stacks with the 5'-terminal of dsDNA by a Leu20-Pro21-Asn22 cluster for precisely trimming the 3'-overhang. In addition, TREX2 specifically interacts with the non-scissile strand of dsDNA by an α-helix-loop region. The unique interaction patterns of the TREX2-dsDNA complex highlight the requirement of long double-stranded region for TREX2 binding and provide evidence of the functional role of TREX2 in processing chromosomal DNA. Moreover, the non-processive property of TREX2 is elucidated by the structure of TREX2-product complex. Our work discloses the first structural basis of the molecular interactions between TREX2 and its substrates and unravels the mechanistic actions of TREX2.