Discovery of S1P/SPHK1 dysregulation in Parkinson’s disease and its role in pathological α-synuclein-induced neurodegeneration

Jiacheng Fang; Xiaoxiao Wang; Xiuli Su; Dan Li; Fuyue Wang; Pengxi Wang; Chenrui Yuan; Fenfen Ji; Doudou Zhang; Xiaodong Cai; Wenlan Liu; Min Li; Shen Hu; Zongwei Cai

doi:10.59717/j.xinn-life.2025.100164

The Innovation Life > 2025 Vol. 3 > No. 4 > 100164

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Discovery of S1P/SPHK1 dysregulation in Parkinson’s disease and its role in pathological α-synuclein-induced neurodegeneration

1.
State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong SAR 999077, China
2.
Eastern Institute of Technology, School of Chemistry, Ningbo 315200, China
3.
Department of Biology, Hong Kong Baptist University, Hong Kong SAR 999077, China
4.
Department of Neurosurgery, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen 518037, China
5.
The Central Laboratory, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen 518037, China
6.
Mr. and Mrs. Ko Chi Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR 999077, China
7.
Jonsson Comprehensive Cancer Center, California NanoSystems Institute, School of Dentistry, University of California, Los Angeles 90024, USA
8.
These authors contributed equally

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Corresponding author: zwcai@hkbu.edu.hk
Received Date: April 09, 2025

Accepted Date: October 13, 2025

Published Online: October 16, 2025

The Innovation Life 3(4), https://doi.org/10.59717/j.xinn-life.2025.100164 | Cite this article

GRAPHICAL ABSTRACT

GRAPHICAL ABSTRACT

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PUBLIC SUMMARY

PUBLIC SUMMARY
1. Sphingosine-1-phosphate is significantly elevated in the cerebrospinal fluid of Parkinson’s disease patients.
  
  Pathologic α-synuclein selectively upregulates microglial SPHK1 over SPHK2.
  
  S1P-mediated NF-κB signaling triggers pathologic α-synuclein-induced microglial activation.
  
  Blockade of SPHK1 attenuates α-synuclein aggregation and neuroinflammation.

ABSTRACT

ABSTRACT

Parkinson's disease (PD) manifests a significant lipidopathy, marked by an enrichment of risk genes involved in sphingolipid metabolism. Sphingolipids are master regulators of cell fate, with sphingosine-1-phosphate (S1P) acting as a key signaling mediator in immunology and vascular biology. However, the fluctuation of S1P metabolism in PD and its role in synucleinopathy-induced neurodegeneration remain poorly understood. In this study, we discovered a 16-fold increase in cerebrospinal fluid (CSF) S1P levels synthesized by sphingosine kinase 1 (SPHK1) in PD patients compared to controls, accompanied by a reduction in sphingosine levels. Similarly, elevated S1P levels are observed in the striatum and midbrain of the α-synuclein preformed fibrils (α-syn PFFs)-induced mouse model of sporadic PD, with Sphk1 exhibiting the most pronounced upregulation among genes categorized under the “sphingosine metabolic process”, while Sphk2 expression remains unchanged. The increase of S1P levels is associated with the selective modulation of SPHK1 in microglia responding to pathological α-synuclein. Of note, α-syn PFFs treatment increases Sphk1 expression and activates SPHK1 in microglia. SPHK1 serves as a key contributor to pathologic α-syn-induced microglial activation via S1P-mediated NF-κB signaling. Knockdown of microglial Sphk1 alleviated neurodegenerative pathology in α-syn PFFs mice alleviates their neuropathological changes. Similarly, inhibition of SPHK1 with PF543 ameliorates PD-like neuropathological abnormalities in hA53T α-synuclein transgenic mice. These findings support a key role of S1P in the pathogenesis of PD linked to pathological α-synuclein.
- Sphingolipids /
- metabolomics /
- neuroinflammation /
- α-synuclein aggregation /
- microgliosis

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Fang J., Wang X., Su X., et al. (2025). Discovery of S1P/SPHK1 dysregulation in Parkinson’s disease and its role in pathological α-synuclein-induced neurodegeneration. The Innovation Life 3:100164. https://doi.org/10.59717/j.xinn-life.2025.100164

Fang J., Wang X., Su X., et al. (2025). Discovery of S1P/SPHK1 dysregulation in Parkinson’s disease and its role in pathological α-synuclein-induced neurodegeneration. The Innovation Life 3:100164. https://doi.org/10.59717/j.xinn-life.2025.100164

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Discovery of S1P/SPHK1 dysregulation in Parkinson’s disease and its role in pathological α-synuclein-induced neurodegeneration

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Discovery of S1P/SPHK1 dysregulation in Parkinson’s disease and its role in pathological α-synuclein-induced neurodegeneration

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