Alpha-synuclein induces microglial migration via PKM2-dependent glycolysis

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Microglial cells activate and adopt an M1 phenotype after spinal cord injury.
• Glucose metabolism reprogramming is linked to microglial activation, but its drivers are unclear.
• Alpha-synuclein's role in microglial glucose metabolism requires elucidation.

Purpose of the Study:

• To investigate the role of alpha-synuclein in regulating aerobic glycolysis in microglia.
• To uncover the underlying mechanisms of alpha-synuclein-mediated glucose reprogramming in microglia.

Main Methods:

• Investigated alpha-synuclein's effect on glycolysis and mitochondrial function.
• Utilized co-immunoprecipitation and Western blot assays to examine alpha-synuclein and PKM2 interaction.
• Assessed the impact of PKM2 knockdown and activation on microglial glycolysis and migration.

Main Results:

• Alpha-synuclein promoted glycolysis and inhibited mitochondrial biogenesis and oxidative phosphorylation in microglia.
• Pyruvate kinase M2 (PKM2) was identified as a key mediator, interacting with alpha-synuclein.
• PKM2 knockdown reduced glycolysis and lactate production, while PKM2 activation enhanced microglial migration.

Conclusions:

• Alpha-synuclein drives microglial glucose metabolism reprogramming through a PKM2-dependent mechanism.
• This highlights a novel pathway involving alpha-synuclein, PKM2, and glycolysis in microglial activation.
• Targeting PKM2 may offer therapeutic potential for conditions involving microglial activation and metabolic dysfunction.