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Characterization and Regulation of Alpha-Synuclein Phosphorylation in Enteric Neurons
Gaëlle Pinard1, Hannah Elena Kunz1, Giuseppe Madaro1
1Nantes Université, CHU Nantes, INSERM, The Enteric Nervous System in Gut and Brain Disorders, Nantes, France.
The European Journal of Neuroscience
|July 17, 2025
Summary
Parkinson's disease protein alpha-synuclein phosphorylation is regulated in enteric neurons via Ca2+-calmodulin-dependent protein kinase and EPAC pathways converging on PLK2. This study reveals new insights into alpha-synuclein regulation in the enteric nervous system.
Area of Science:
- Neuroscience
- Molecular Biology
- Gastroenterology
Background:
- Alpha-synuclein is a neuronal protein linked to Parkinson's disease (PD), with serine 129 phosphorylation being a key modification.
- While alpha-synuclein phosphorylation occurs in the central nervous system, its regulation and role in the enteric nervous system (ENS) are largely unexplored.
- The ENS is increasingly recognized for its complex neural functions, making it a critical area for investigation.
Purpose of the Study:
- To investigate the regulation of alpha-synuclein phosphorylation in enteric neurons.
- To identify the signaling pathways involved in alpha-synuclein phosphorylation within the ENS.
- To explore the potential differences in phosphorylated alpha-synuclein in human colon samples from PD and control subjects.
Main Methods:
- Primary cultures of rat enteric nervous system (ENS) and enteric neurons were used.
- Cells were subjected to membrane depolarization or forskolin treatment.
- Western blot analysis was performed to detect alpha-synuclein phosphorylation.
- Human colon specimens were analyzed for phosphorylated alpha-synuclein distribution.
Main Results:
- Membrane depolarization induced alpha-synuclein phosphorylation via a Ca2+-calmodulin-dependent protein kinase pathway.
- Forskolin treatment induced alpha-synuclein phosphorylation via a cAMP/EPAC signaling pathway.
- Both pathways converged on Polo-like kinase 2 (PLK2) for alpha-synuclein phosphorylation.
- PLK2 inhibition increased alpha-synuclein secretion and decreased its intracellular phosphorylation.
- Phosphorylated alpha-synuclein distribution in the human ENS was highly variable.
- No significant difference in soluble phosphorylated alpha-synuclein was found between PD and control subjects.
Conclusions:
- Alpha-synuclein phosphorylation is regulated in enteric neurons through distinct signaling pathways.
- PLK2 plays a crucial role in the phosphorylation and secretion of alpha-synuclein in the ENS.
- This study provides a foundation for understanding the function of alpha-synuclein and its phosphorylation in the ENS.
- While linked to PD, alpha-synuclein phosphorylation levels in the human ENS did not differ between PD and control groups in this study.
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