NAD+ - and EVA1-C-dependent reversal of neurological deficits is mediated by differential alternative RNA splicing in tauopathic animal models

Ruixue Ai; Lipeng Mao; Xurui Jin; Shiqi Zhang; Junping Pan; Mariá José Lagartos-Donate; Shuqin Cao; Guang Yang; Chenglong Xie; Xiongbin Kang; Pingjie Wang; Yang Hu; Linda Hildegard Bergersen; Jon Storm‐Mathisen; Hidehito Kuroyanagi; Beatriz Escobar-Doncel; Noemí Villaseca González; Farrukh Abbas Chaudhry; Zeyuan Wang; Qiang Zhang; Zhangming Niu; Guobing Chen; Oscar Junhong Luo; Evandro Fei Fang

doi:10.1101/2024.10.27.620478

NeurosciencebioRxivOct 27, 2024

Preprint

NAD+ - and EVA1-C-dependent reversal of neurological deficits is mediated by differential alternative RNA splicing in tauopathic animal models

Ruixue Ai iD, Lipeng Mao iD, Xurui Jin iD, Shiqi Zhang iD, Junping Pan iD, Mariá José Lagartos-Donate iD, Shuqin Cao iD, Guang Yang iD, Chenglong Xie iD, Xiongbin Kang iD, Pingjie Wang iD, Yang Hu iD, Linda Hildegard Bergersen iD, Jon Storm‐Mathisen iD, Hidehito Kuroyanagi iD, Beatriz Escobar-Doncel iD, Noemí Villaseca González iD, Farrukh Abbas Chaudhry iD, Zeyuan Wang iD, Qiang Zhang iD, Zhangming Niu iD, Guobing Chen iD, Oscar Junhong Luo iD, Evandro Fei Fang iD

Abstract

Aberrant alternative splicing (ASEs) is an aging hallmark to Alzheimers Disease (AD). Although NAD+ and related metabolites can slow down AD, NAD+ on ASEs in AD remain unclear. Mouse transcriptomic data revealed NR-induced ASEs, focusing on the Eva1-C locus. AI-based algorithms predicted EVA1-C protein structures and protein-protein interactions. AD postmortem brain samples and tauopathy models including transgenic mice and worm was used for validation. NAD+ abundance/metabolic status modulates ASEs and the expression of EVA1-C isoforms, which in turn regulate the interaction with BAG-1 and HSP70 proteins. Importantly, EVA1-C is dramatically reduced in 20 Braak 5/6 AD patients compared to cognitive normal humans in different brain regions. NAD+ metabolism modulates abundance of specific mRNA isoforms, and that ASEs influence disease progression in model tauopathies and potentially AD. These results could facilitate future development of NAD+-based splice-switching therapeutics for AD. TeaserUnveiling the Link Between NAD+ Metabolism and Alzheimers Disease: Discovering the Role of Alternative RNA Splicing in Disease Progression and Potential Therapeutic Targets

PDF DOI