PXD048769

PXD048769 is an original dataset announced via ProteomeXchange.

Title	ACSS2 Upregulation Enhances Neuronal Resilience to Aging and Neurodegeneration
Description	Epigenetic mechanisms, including histone acetylation, play a key role in learning and memory, with recent evidence of a role in neuronal function in Alzheimer’s disease and Related Dementia (ADRD). Acetyl-CoA sythetase 2 (ACSS2) is central to epigenetics and gene regulation, particularly in neurons, due to their unique metabolic demands and their postmitotic state. ACSS2 can be directly recruited to the nucleus to locally supply acetyl-CoA, and to directly fuel histone acetyltransferases. This gene regulatory mechanism presents a promising avenue for targeted therapeutic interventions in neurodegenerative diseases. Building upon our prior discovery that systemic ACSS2 deletion in mouse impairs memory and reduces immediate early gene expression, we explored whether increasing levels of ACSS2 to boost chromatin processes could protect neurons against disease and age-associated cognitive decline. Given the role of tau in ADRD, we used primary hippocampal neurons that mimic the sporadic development of tau pathology, and the PS19 transgenic mouse model for tau-induced memory decline. We show that ACSS2 upregulation mitigates tau-induced transcriptional alterations, enhances neuronal resilience against tau pathology, improves long-term potentiation, and ameliorates memory deficits. Expanding upon our findings, we investigated ACSS2-dependent epigenetic modifications in aged mice. Our results reveal that increasing histone acetylation through ACSS2 upregulation also improves age-associated memory decline. These findings show that increasing the level of ACSS2 is highly effective in countering age and tau-induced transcriptomic changes, preserving elevated levels of synaptic genes, and thereby safeguards synaptic integrity over time. Our results highlight ACSS2 as a key player in the epigenetic regulation of cognitive aging and ADRD, thus opening exciting prospects for targeted therapeutic strategies aimed at enhancing brain resilience and function.
HostingRepository	PRIDE
AnnounceDate	2026-09-07
AnnouncementXML	Submission_2026-09-06_16:11:26.602.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Michael Gilbert
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	monomethylated residue; acetylated residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2024-01-22 10:27:41	ID requested
⏵ 1	2026-09-06 16:11:27	announced

Pourshafie N, Alexander DC, Xu H, Yang K, Donahue G, Lei X, Zhang S, Shcherbakova O, Hogan C, Gilbert M, Hoxha K, Chaboub L, Lee VM, Adams PD, Dani JA, Bonini NM, Berger SL, ACSS2 upregulation enhances neuronal resilience to aging and tau-associated neurodegeneration. Proc Natl Acad Sci U S A, 123(2):e2503834122(2026) [pubmed]

10.1073/pnas.2503834122;

submitter keyword: ACSS2, Aging, Neuron, Neurodegeneration

Shelley Lynn Berger
contact affiliation	University of Pennsylvania, Cell and Developmental Biology, Epigenetics Institute
contact email	bergers@pennmedicine.upenn.edu
lab head
Michael Gilbert
contact affiliation	University of Pennsylvania
contact email	gilbertbmichael@gmail.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD048769
     1. Label: PRIDE project
     2. Name: ACSS2 Upregulation Enhances Neuronal Resilience to Aging and Neurodegeneration