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

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.

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Publication Details

Journal
Neuron
Published
2025-04-21
DOI
https://doi.org/10.1016/j.neuron.2025.03.028
Citations
9
Primary Topic
Parkinson's Disease Mechanisms and Treatments
Type
article
Field-Weighted Citation Impact
12.50

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article

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

David C. Rubinsztein, Sung Min Son, Rizwan Ansari, Farah H. Siddiqi et al.
9 citations
Neuron
Parkinson's Disease Mechanisms and Treatments
12.50
article

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

David C. Rubinsztein, Sung Min Son, Rizwan Ansari, Farah H. Siddiqi, Angeleen Fleming, Tilo Kunath, Sylwia D. Tyrkalska, Emmanouil Metzakopian, Ana López, So Jung Park
article en
9 citations

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.

NeuronVol. 113(12)
Babraham Institute (GB), Wellcome/MRC Cambridge Stem Cell Institute (GB), University of Cambridge (GB), MRC Centre for Regenerative Medicine (GB), UK Dementia Research Institute (GB), Institute for Medical Research (MY), University of Edinburgh (GB)
Guarantors of Brain, Rosetrees Trust, UK Dementia Research Institute, John Black Charitable Foundation, Medical Research Council, Horizon 2020, NIHR Cambridge Biomedical Research Centre
Zero hunger
Openalex Percentile: Top 1%
Parkinson's Disease Mechanisms and Treatments
12.50
DOIOpen Access PDFOpenAlex
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