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. 2025 Jun 18;113(12):1908-1924.e13.
doi: 10.1016/j.neuron.2025.03.028. Epub 2025 Apr 21.

Alpha-synuclein mutations mislocalize cytoplasmic p300 compromising autophagy, which is rescued by ACLY inhibition

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Free article

Alpha-synuclein mutations mislocalize cytoplasmic p300 compromising autophagy, which is rescued by ACLY inhibition

Sung Min Son et al. Neuron. .
Free article

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.

Keywords: ACLY; AMPK; Parkinson's disease; acetyl-CoA; acetylation; alpha-synuclein; autophagy; mTORC1; nucleocytoplasmic shuttling of p300.

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Conflict of interest statement

Declaration of interests D.C.R. is a consultant for Aladdin Healthcare Technologies Ltd., Mindrank AI, Nido Biosciences, Drishti Discoveries, Carlyle Investment Management LLC, Alexion Pharma International Operations Limited, and PAQ Therapeutics. E.M. is chief scientific officer and shareholder of bit.bio.

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