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.

University of Oslo · biorxiv

Paper

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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Research summary

The paper explores the relationship between NAD+ metabolism and alternative RNA splicing in the context of Alzheimer's Disease, which is a significant age-related condition. While it addresses mechanisms that could contribute to disease progression, it primarily focuses on treatment strategies rather than directly targeting the root causes of aging. The findings are solid and contribute to the understanding of molecular mechanisms in tauopathies, but they do not represent a major breakthrough or transformative implications for longevity research.

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