Nuclear acetyl-CoA accumulation drives reversible RBP hyperacetylation and transcriptome-wide splicing shifts in age-equivalent Alzheimer's disease neurons
- 1University of California San Diego
Abstract
Metabolic alterations and dysregulated alternative RNA splicing are central layers of Alzheimer's disease (AD) pathogenesis, yet whether and to what extent these changes are mechanistically linked in adult human neurons in the aging brain remains unclear. To assess this, we generated induced neurons (iNs) by direct conversion of fibroblasts from sporadic AD patients and age-matched control donors. Fibroblast-derived iNs retaining donor-specific aging signatures have been shown to display several AD-related phenotypes. Metabolomic analysis revealed that AD iNs divert citrate toward ATP-citrate lyase (ACLY)-dependent citrate-to-acetyl-CoA flux, which drives increased nuclear levels of the high-energy metabolite acetyl-CoA. Acetyl-proteomics showed that acetyl-CoA accumulation leads to widespread hyper-acetylation of RNA-binding proteins (RBPs) and splice regulators, suggestive of a direct mechanistic link between a metabolic shift and RNA processing. Indeed, single-cell long-read RNA sequencing identifies splicing alterations in AD-relevant transcripts whose isoform usage mirrors changes observed in post-mortem AD cortex samples. Subcellular acetyl-CoA imaging reveals that inhibition of ACLY enzymatic activity selectively reduces nuclear acetyl-CoA levels, and further improves citrate metabolic flux, normalizes RBP acetylation, and re-establishes a normal neuronal splicing landscape in AD iNs. Together, these findings reveal a nuclear acetyl-CoA-RNA processing axis that links age- and disease-related metabolic alterations to alternative splicing dysregulation in AD, and identify neuronal nuclear acetyl-CoA production as a causal and reversible node for restoring metabolic and RNA homeostasis in aging human AD neurons.
Related
- Dim blue light drives reversible fucoxanthin derivative accumulation in the pelagophyte Pelagomonas calceolata
- Zika virus infection induces a persistent accumulation of Alzheimer’s disease-like Tau phosphorylation in adult immunocompetent mice in association with memory and social behavior impairments
- Optimizing SAR-SGC protocol for equivalent dose determination in quartz luminescence dating
- Male and female mice achieve equivalent protection against heterologous SARS-CoV-2 infection through divergent immune mechanisms
- Spinal Noradrenergic Overdrive Promotes Reversible Motor Unit Aging and Sarcopenia
BibTeX
@misc{traxler2026nuclear,
title = {{Nuclear acetyl-CoA accumulation drives reversible RBP hyperacetylation and transcriptome-wide splicing shifts in age-equivalent Alzheimer's disease neurons}},
author = {L. Traxler and O. Borgogno and K. Champion and J. R. Herdy and M. Dzieciatkowska and J. A. Reisz and A. Petrosyan and C. Siler and C. C. Anderson and E. Gorostieta-Salas and R. Lucciola and D. Galasko and F. H. Gage and A. D Alessandro and J. Mertens},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.26.754222},
url = {https://www.biorxiv.org/content/10.64898/2026.09.26.754222v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Nuclear acetyl-CoA accumulation drives reversible RBP hyperacetylation and transcriptome-wide splicing shifts in age-equivalent Alzheimer's disease neurons
AU - L. Traxler
AU - O. Borgogno
AU - K. Champion
AU - J. R. Herdy
AU - M. Dzieciatkowska
AU - J. A. Reisz
AU - A. Petrosyan
AU - C. Siler
AU - C. C. Anderson
AU - E. Gorostieta-Salas
AU - R. Lucciola
AU - D. Galasko
AU - F. H. Gage
AU - A. D Alessandro
AU - J. Mertens
PY - 2026
DA - 2026/09/26
PB - bioRxiv
DO - 10.64898/2026.09.26.754222
UR - https://www.biorxiv.org/content/10.64898/2026.09.26.754222v1
AB - Metabolic alterations and dysregulated alternative RNA splicing are central layers of Alzheimer's disease (AD) pathogenesis, yet whether and to what extent these changes are mechanistically linked in adult human neurons in the aging brain remains unclear. To assess this, we generated induced neurons (iNs) by direct conversion of fibroblasts from sporadic AD patients and age-matched control donors. Fibroblast-derived iNs retaining donor-specific aging signatures have been shown to display several AD-related phenotypes. Metabolomic analysis revealed that AD iNs divert citrate toward ATP-citrate lyase (ACLY)-dependent citrate-to-acetyl-CoA flux, which drives increased nuclear levels of the high-energy metabolite acetyl-CoA. Acetyl-proteomics showed that acetyl-CoA accumulation leads to widespread hyper-acetylation of RNA-binding proteins (RBPs) and splice regulators, suggestive of a direct mechanistic link between a metabolic shift and RNA processing. Indeed, single-cell long-read RNA sequencing identifies splicing alterations in AD-relevant transcripts whose isoform usage mirrors changes observed in post-mortem AD cortex samples. Subcellular acetyl-CoA imaging reveals that inhibition of ACLY enzymatic activity selectively reduces nuclear acetyl-CoA levels, and further improves citrate metabolic flux, normalizes RBP acetylation, and re-establishes a normal neuronal splicing landscape in AD iNs. Together, these findings reveal a nuclear acetyl-CoA-RNA processing axis that links age- and disease-related metabolic alterations to alternative splicing dysregulation in AD, and identify neuronal nuclear acetyl-CoA production as a causal and reversible node for restoring metabolic and RNA homeostasis in aging human AD neurons.
ER -