研究業績
bioRxiv
NAD+ - and EVA1-C-dependent reversal of neurological deficits is mediated by differential alternative RNA splicing in tauopathic animal models.
著者
Ruixue Ai, Lipeng Mao, Xurui Jin, Shi-qi Zhang, Junping Pan, Maria Jose Donate Lagartos, Shu-Qin 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
カテゴリ
PrePrint
Abstract
Aberrant alternative splicing (ASEs) is an aging hallmark to Alzheimer’s 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.
