Microglia toxicology in α-synuclein pathology

Area of Science:

• Neuroscience
• Immunology
• Cell Biology

Background:

• Oligomeric alpha-synuclein (α-syn) is implicated in Parkinson's disease (PD) pathogenesis through microglial activation and inflammation.
• Previous research indicated altered IL6ST levels in PD patients and a decline in the IL6ST/JAK2/STAT3 pathway in α-syn-stimulated microglia.
• The JAK2/STAT3 pathway is recognized for its role in inflammation and ferroptosis.

Purpose of the Study:

• To investigate the role of the IL6ST/JAK2/STAT3 pathway in α-syn-induced microglial dysfunction and ferroptosis.
• To elucidate the mechanisms by which α-syn affects microglial activity, polarization, and ferroptosis.

Main Methods:

• Utilized α-syn-induced HMC3 cells (a human immortalized microglia cell line).
• Performed transcriptomic analysis and Gene Set Enrichment Analysis (GSEA).
• Assessed cell activity, M2 phenotype differentiation, mitochondrial morphology, and levels of iron metabolism and lipid peroxidation. Investigated the effect of a STAT3 activator.

Main Results:

• α-syn impaired HMC3 cell activity and promoted M2 polarization.
• α-syn inhibited the IL6ST/JAK2/STAT3 pathway and its downstream target HIF-1α.
• Transcriptomic analysis revealed an association between α-syn stimulation and ferroptosis pathways.
• α-syn decreased STAT3 phosphorylation, leading to mitochondrial changes and upregulation of ferroptosis genes (ASCL4, SLC7A11).
• α-syn promoted microglial ferroptosis by inhibiting P-STAT3 and increasing iron metabolism and lipid peroxidation, effects reversed by a STAT3 activator.

Conclusions:

• STAT3 phosphorylation and activation are critical regulators of microglia ferroptosis in the context of α-syn stimulation.
• α-syn influences microglial cell activity, polarization, and ferroptosis via the IL6ST/JAK2/STAT3/HIF-1α axis.