Summary
A bioRxiv preprint reports that increased nuclear acetyl-CoA in lab-grown neurons from people with sporadic Alzheimer’s disease was linked to altered RNA-protein acetylation and splicing. Inhibiting the enzyme ACLY reversed these changes in the cell model.
A bioRxiv preprint reports that elevated nuclear acetyl-CoA was associated with widespread changes to RNA-binding proteins and RNA splicing in lab-grown neurons derived from people with sporadic Alzheimer’s disease. The researchers also report that inhibiting ATP-citrate lyase (ACLY), an enzyme involved in producing acetyl-CoA from citrate, reversed these molecular changes in the cells.
The team made induced neurons by directly converting skin fibroblasts from people with sporadic Alzheimer’s disease and age-matched control donors. The abstract does not state how many donors were included. These lab-grown cells provide a way to study donor-associated features in neurons; they are not neurons sampled directly from patients’ brains.
How metabolism may influence RNA processing
Acetyl-CoA is a molecule used in cellular metabolism and also supplies acetyl groups for modifying proteins. RNA-binding proteins attach to RNA and help regulate how it is processed. In alternative splicing, cells assemble RNA from the same gene in different ways, producing distinct transcript forms, or isoforms.
The researchers’ metabolomic analysis found that Alzheimer’s model neurons diverted citrate into ACLY-dependent acetyl-CoA production, with increased acetyl-CoA in the nucleus. Their acetyl-proteomics analysis found widespread hyperacetylation—higher levels of acetyl-group modification—among RNA-binding proteins and splicing regulators. Together, these results point to a possible route by which a change in cellular metabolism could alter RNA processing.
Single-cell long-read RNA sequencing identified splicing changes in transcripts relevant to Alzheimer’s disease. The authors report that the isoform patterns resembled changes seen in post-mortem Alzheimer’s cortex samples. Long-read sequencing can read longer stretches of RNA, helping distinguish different transcript isoforms.
ACLY inhibition reversed changes in the cell model
The team used imaging to track acetyl-CoA in different parts of the cell. Inhibiting ACLY reduced nuclear acetyl-CoA, and the researchers report that this intervention also improved citrate metabolic flux, normalized RNA-binding-protein acetylation and restored a more typical neuronal splicing pattern in the Alzheimer’s induced neurons.
The findings connect a metabolic change with RNA processing in a human-cell-derived model and identify nuclear acetyl-CoA production as a potentially reversible point in that chain. The work is a preprint, and its results concern changes in lab-grown cells. They do not establish that ACLY inhibition can slow Alzheimer’s disease or improve outcomes in people.