Sphingolipid-Neuroinflammation Axis in Parkinson's Disease: Focus on S1P/SPHK1-NF‑κB Signaling

Area of Science:

• Neuroscience
• Biochemistry
• Immunology

Background:

• Parkinson's disease (PD) involves dopaminergic neuron loss, alpha-synuclein aggregation, and neuroinflammation.
• Sphingosine-1-phosphate (S1P), regulated by sphingosine kinase 1 (SPHK1), plays a role in immune responses and cell survival.
• Nuclear factor-kappaB (NF-κB) is crucial in neuroinflammation, influencing cytokine release and microglial activation.

Purpose of the Study:

• To systematically review the molecular basis and cell-specific mechanisms of the S1P/SPHK1-NF-κB signaling axis in PD.
• To explore the axis's crosstalk with alpha-synuclein pathology, mitochondrial dysfunction, blood-brain barrier integrity, and gut-brain axis.
• To summarize the potential of this axis as a diagnostic biomarker and therapeutic target for PD.

Main Methods:

• Systematic literature review of preclinical and clinical studies.
• Analysis of molecular pathways and cell-specific mechanisms.
• Evaluation of existing data on S1P levels and SPHK1 activity in PD.

Main Results:

• Elevated S1P levels and activated SPHK1 are observed in PD patients.
• The S1P/SPHK1-NF-κB axis correlates with alpha-synuclein pathology, neuroinflammation, and dopaminergic neuron degeneration.
• Mechanistic ambiguities and translational hurdles in targeting this axis remain.

Conclusions:

• The S1P/SPHK1-NF-κB axis is implicated in PD pathogenesis, interacting with key pathological features.
• This axis presents potential as a diagnostic biomarker and therapeutic target, but requires further investigation.
• Addressing bottlenecks like standardization and interspecies discrepancies is crucial for clinical translation.