Alpha-Synuclein Mutations Mislocalize Cytoplasmic p300 Compromising Autophagy, Which Is Rescued by ACLY Inhibition

Neurology Medicine
Alpha-Synuclein Autophagy ACLY Inhibition Parkinson's Disease p300 mTORC1 Neuronal Models

Academic Background

Parkinson’s Disease (PD) is the second most common neurodegenerative disorder, characterized by motor dysfunction, loss of dopaminergic neurons, and abnormal accumulation of alpha-synuclein (α-syn). Although the cause of most PD cases remains unclear, approximately 5%-10% of cases are due to monogenic mutations. The SNCA gene, which encodes α-synuclein, was the first gene discovered to be associated with autosomal dominant PD. SNCA mutations typically lead to early-onset PD, with the A53T mutation being one of the most common point mutations. However, the mechanisms by which α-synuclein induces neurodegeneration remain poorly understood.

Autophagy is a crucial intracellular process for clearing damaged proteins and organelles and is one of the primary pathways for α-synuclein degradation. Studies have shown that overexpression or mutations of α-synuclein inhibit autophagy, leading to the accumulation of α-synuclein and the onset of PD symptoms. Therefore, understanding how α-synuclein affects the autophagy process and identifying potential therapeutic targets to restore autophagy function is of great significance for PD treatment.

Source of the Paper

This paper was co-authored by Sung Min Son, Farah H. Siddiqi, Ana Lopez, and others, with the primary authors affiliated with the Cambridge Institute for Medical Research (CIMR) and the UK Dementia Research Institute. The paper was published on June 18, 2025, in the journal Neuron, titled “α-Synuclein Mutations Mislocalize Cytoplasmic p300 Compromising Autophagy, Which Is Rescued by ACLY Inhibition.”

Research Process and Results

1. α-Synuclein Mutations Activate ACLY, Affecting p300 Cytoplasmic Localization

The researchers first observed in SH-SY5Y neuroblastoma cells expressing A53T α-synuclein that the A53T mutation led to increased levels of acetyl-CoA in the cytoplasm and decreased acetylation of histones in the nucleus. Through mass spectrometry and immunoblotting experiments, the researchers found that the A53T mutation activated ATP-citrate lyase (ACLY), a key enzyme responsible for generating acetyl-CoA in the cytoplasm. Further experiments demonstrated that ACLY activation enhanced the activity of cytoplasmic p300, an important acetyltransferase that acetylates various proteins, including raptor, a component of the mechanistic target of rapamycin complex 1 (mTORC1).

2. Cytoplasmic Localization of p300 Leads to mTORC1 Hyperactivation, Inhibiting Autophagy

The researchers discovered that A53T α-synuclein, by activating ACLY, increased the activity of cytoplasmic p300, leading to the acetylation of raptor and the activation of mTORC1. mTORC1 is a key regulator of cell growth, metabolism, and autophagy, and its hyperactivation inhibits the autophagy process. Through immunofluorescence and immunoblotting experiments, the researchers confirmed that the A53T mutation reduced levels of the autophagy marker LC3-II, indicating impaired autophagy function.

3. ACLY Inhibitors Restore Autophagy Function and Reduce α-Synuclein Aggregation

To validate the role of ACLY in PD pathology, the researchers used specific ACLY inhibitors, hydroxycitrate (HC) and SB-204990. Experimental results showed that ACLY inhibitors restored autophagy function in cells expressing A53T α-synuclein and reduced α-synuclein aggregation. Additionally, ACLY inhibitors alleviated pathological phenotypes such as DNA damage, mitochondrial dysfunction, and apoptosis in neurons.

4. Validation of ACLY Inhibition’s Therapeutic Effects in Zebrafish and Mouse Models

The researchers further validated the effects of ACLY inhibitors in A53T α-synuclein transgenic zebrafish and mouse models. The results showed that ACLY inhibitors reduced the phosphorylation and aggregation of α-synuclein in the brains of zebrafish and mice, restored autophagy function, and improved neuronal survival. These findings suggest that ACLY inhibitors have potential therapeutic effects for PD in vivo.

Conclusion and Significance

This study reveals the molecular mechanism by which α-synuclein mutations activate ACLY, leading to abnormal cytoplasmic localization of p300, mTORC1 hyperactivation, and autophagy inhibition. By using ACLY inhibitors, the researchers successfully restored autophagy function, reduced α-synuclein aggregation, and improved pathological phenotypes in PD models. This discovery not only provides new insights into the pathogenesis of PD but also offers a theoretical basis for developing ACLY-targeted PD therapies.

Research Highlights

  1. First Identification of ACLY’s Role in PD Pathology: The study found that ACLY is a key molecule in α-synuclein mutation-induced autophagy inhibition, providing a new therapeutic target for PD.
  2. Therapeutic Effects of ACLY Inhibitors: Experiments demonstrated that ACLY inhibitors restore autophagy function, reduce α-synuclein aggregation, and show significant therapeutic effects in zebrafish and mouse models.
  3. Multi-Model Validation: The study validated the therapeutic effects of ACLY inhibitors in multiple models, including cells, zebrafish, and mice, enhancing the reliability of the findings.

Additional Valuable Information

The study also found that ACLY inhibits AMPK (AMP-activated protein kinase) by acetylating LKB1 (liver kinase B1), thereby affecting the nuclear-cytoplasmic distribution of p300. This finding provides a new perspective on how ACLY regulates cellular metabolism and autophagy.

This study not only elucidates the molecular mechanisms by which α-synuclein mutations inhibit autophagy but also identifies a new potential therapeutic target for PD, holding significant scientific and clinical value.