Postdoctoral Fellow University of California, San Diego (UCSD), United States
Abstract: Aging is the primary risk factor for Alzheimer’s disease (AD), a devastating neurodegenerative disorder marked by progressive neuronal loss. Healthy neurons typically possess intrinsic mechanisms that confer resilience to external stressors, enabling survival over decades. Our previous studies using induced neurons (iNs) directly converted from patient fibroblasts, revealed that metabolic reprogramming in AD disrupts these mechanisms, leading to compromised neuronal resilience. As iNs retain transcriptional and metabolic features of aging and AD, they serve as an ideal model to study human neuron-specific mechanisms of age-related neurodegeneration. In this study, we used iNs from sporadic AD patients and age- and sex-matched controls to identify druggable metabolic pathways underlying the loss of neuronal resilience in AD. UHPLC-MS metabolomics and genetically encoded metabolic sensors revealed a diversion of citrate from the mitochondrial TCA cycle toward nuclear acetyl-CoA production via ATP-citrate lyase (ACLY). This metabolic shift caused hyperacetylation of RNA-binding proteins (RBPs), disrupting RNA splicing. To further explore the impact of ACLY-mediated acetyl-CoA generation on RNA splicing, we employed a novel single-cell long-read RNA sequencing approach. This innovate technique previously demonstrated that human neurons express distinct RNA isoform patterns critical to their function and identity. These patterns, which are unique to the human brain and absent in animal models, partly explain the differing susceptibility of humans and mice to neurodegeneration, emphasizing the value of studying human cells to understand neurodegenerative diseases. In AD iNs, we identified splicing changes linked to cell death and neuronal dysfunction. Crucially, ACLY inhibition that reduced nuclear acetyl-CoA levels, also restored a healthy neuronal isoform landscape, and reversed splicing alterations specifically driven by hyperacetylated RBPs. These findings reveal a metabolic mechanism driving splicing defects in AD and highlight targeting acetyl-CoA dynamics as a promising therapeutic strategy.
Funding Source: BirghtFocus Foundation A20222024F, Theodor Koerner Fonds, L'Oreal Austria/OeUK/OwAW
