Fig. 7.

Proposed mechanism of surface P2X4 upregulation and consequences in ALS. In normal conditions P2X4 is constitutively endocytosed by the binding of AP2 on its C-terminus internalization domain resulting in a low surface expression restricted to MN within the spinal cord. During ALS progression, (1) misfolded mutant proteins like SOD1 or TDP-43 interfere with P2X4 internalization by competing for AP2 interaction leading to an increase in surface P2X4 density in cells expressing P2X4 such as MNs and macrophages at early stages. (2) At symptomatic stages de novo P2X4 expression in spinal reactive microglia further increase P2X4 signaling in microglia. Cell-specific and time-dependent activation of P2X4 is critical for beneficial or detrimental effects on ALS