PUBLICATION
Alpha-synuclein mutations mislocalize cytoplasmic p300 compromising autophagy, which is rescued by ACLY inhibition
- Authors
- Son, S.M., Siddiqi, F.H., Lopez, A., Ansari, R., Tyrkalska, S.D., Park, S.J., Kunath, T., Metzakopian, E., Fleming, A., Rubinsztein, D.C.
- ID
- ZDB-PUB-250423-6
- Date
- 2025
- Source
- Neuron : (Journal)
- Registered Authors
- Fleming, Angeleen
- Keywords
- ACLY, AMPK, Parkinson's disease, acetyl-CoA, acetylation, alpha-synuclein, autophagy, mTORC1, nucleocytoplasmic shuttling of p300
- MeSH Terms
-
- E1A-Associated p300 Protein*/metabolism
- Mice
- Zebrafish
- Animals
- Autophagy*/drug effects
- Autophagy*/genetics
- Autophagy*/physiology
- Humans
- Neurons/metabolism
- Parkinson Disease*/genetics
- Parkinson Disease*/metabolism
- Parkinson Disease*/pathology
- Cytoplasm/metabolism
- alpha-Synuclein*/genetics
- alpha-Synuclein*/metabolism
- Mechanistic Target of Rapamycin Complex 1/metabolism
- Mutation/genetics
- PubMed
- 40262613 Full text @ Neuron
Citation
Son, S.M., Siddiqi, F.H., Lopez, A., Ansari, R., Tyrkalska, S.D., Park, S.J., Kunath, T., Metzakopian, E., Fleming, A., Rubinsztein, D.C. (2025) Alpha-synuclein mutations mislocalize cytoplasmic p300 compromising autophagy, which is rescued by ACLY inhibition. Neuron. :.
Abstract
Triplications and certain point mutations in the SNCA gene, encoding alpha-synuclein (α-Syn), cause Parkinson's disease (PD). Here, we demonstrate that the PD-causing A53T α-Syn mutation and elevated α-Syn expression perturb acetyl-coenzyme A (CoA) and p300 biology in human neurons and in the CNS of zebrafish and mice. This dysregulation is mediated by activation of ATP-citrate lyase (ACLY), a key enzyme that generates acetyl-CoA in the cytoplasm, via two mechanisms. First, ACLY activity increases acetyl-CoA levels, which activate p300. Second, ACLY activation increases LKB1 acetylation, which inhibits AMPK, leading to increased cytoplasmic and decreased nuclear p300. This lowers histone acetylation and increases acetylation of cytoplasmic p300 substrates, like raptor, which causes mechanistic target of rapamycin complex 1 (mTORC1) hyperactivation, thereby impairing autophagy. ACLY inhibitors rescue pathological phenotypes in PD neurons, organoids, zebrafish, and mouse models, suggesting that this pathway is a core feature of α-Syn toxicity and that ACLY may be a suitable therapeutic target.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping