A Review in the Journal of Neuroinflammation summarizes key factors and mechanisms contributing to lysosomal acidification impairment, the associated dysfunction in microglia, and how these defects contribute to neuroinflammation and neurodegeneration.
Factors affecting microglial lysosomal acidification and associated phagocytic and autophagic function.Presenilin-1 deficient in phosphorylation at Ser367 leads to reduced ATP6V0a1 levels, impairing lysosomal acidification. Furthermore, PS1 S367A reduces binding to Annexin A2 and decreases VAMP8 binding to autophagosomal Syntaxin 17, thereby preventing autophagosome-lysosome fusion, leading to autophagic inhibition.
Extracellular ATP activate P2X7R, leading to influx of Ca, accumulation of autophagosomes, elevation of lysosomal pH as well as increased cytokine release via inflammasome. On the other hand, inhibition of P2X4R by TNP-ATP results in increased cytokine release, while activation of P2X4R by ivermectin improves lysosomal acidification and promotes microglial function.
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