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

Ai, R.; Mao, L.; Jin, X.; Zhang, S.-q.; Pan, J.-p.; Lagartos, M. J. D.; Cao, S.-Q.; Yang, G.; Xie, C.; Kang, X.; Wang, P.; Hu, Y.; Bergersen, L. H.; Storm-Mathisen, J.; Kuroyanagi, H.; Doncel, B. E.; Gonzalez, N. V.; Chaudhry, F. A.; Wang, Z.; Zhang, Q.; Niu, Z.; Chen, G.; Luo, O. J.; Fang, E. F.

doi:10.1101/2024.10.27.620478

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bioRxiv · 10.1101/2024.10.27.620478

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

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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

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Ai, R., Mao, L., Jin, X., Zhang, S.-q., Pan, J.-p., Lagartos, M. J. D., Cao, S.-Q., Yang, G., Xie, C., Kang, X., Wang, P., Hu, Y., Bergersen, L. H., Storm-Mathisen, J., Kuroyanagi, H., Doncel, B. E., Gonzalez, N. V., Chaudhry, F. A., Wang, Z., Zhang, Q., Niu, Z., Chen, G., Luo, O. J., Fang, E. F.. 2024-10-28. NAD+ - and EVA1-C-dependent reversal of neurological deficits is mediated by differential alternative RNA splicing in tauopathic animal models. https://doi.org/10.1101/2024.10.27.620478

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