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

  1. Ruixue Ai
  2. Lipeng Mao
  3. Xurui Jin
  4. Shi-qi Zhang
  5. Junping Pan
  6. Maria Jose Donate Lagartos
  7. Shu-Qin Cao
  8. Guang Yang
  9. Chenglong Xie
  10. Xiongbin Kang
  11. Pingjie Wang
  12. Yang Hu
  13. Linda Hildegard Bergersen
  14. Jon Storm-Mathisen
  15. Hidehito Kuroyanagi
  16. Beatriz Escobar Doncel
  17. Noemí Villaseca González
  18. Farrukh Abbas Chaudhry
  19. Zeyuan Wang
  20. Qiang Zhang
  21. Zhangming Niu
  22. Guobing Chen
  23. Oscar Junhong Luo
  24. Evandro Fei Fang
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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.

Teaser

Unveiling the Link Between NAD+Metabolism and Alzheimer’s Disease: Discovering the Role of Alternative RNA Splicing in Disease Progression and Potential Therapeutic Targets

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