The regulation of proteostasis in glial cells by nucleotide receptors is key in acute neuroinflammation.

The disturbances of cellular proteostasis caused by the alteration in the ubiquitin-proteasome system (UPS) have been proposed as a common mechanism underlying several neural pathologies that involve a neuroinflammatory process. As we have previously reported that the nucleotide receptor P2Y purinoceptor 2 (P2Y2 R) regulates the proteasomal catalytic activities, we wonder whether this receptor is involved in the UPS disturbances associated with the neuroinflammation process. With the use of mice expressing a UPS reporter [mice expressing the UPS reporter ubiquitinG76V -green fluorescent protein (UbGFP mice)], we found that LPS-induced acute neuroinflammation status causes a UPS impairment in astrocytes and microglial cells by a mechanism dependent on P2Y2 R. In this line, LPS-treated double transgenic UbGFP; P2Y2 R-/- mice did not present a UPS impairment in astrocytes or a social interaction deficit as severe as that observed in LPS-treated UbGFP mice. In vivo administration of selective P2Y2 R agonist diuridine tetraphosphate reversed the UPS impairment completely in astrocytes and partially in microglial cells, promoting increased expression of the proteasomal β5 subunit by a mechanism dependent on the Src/PI3K/ERK pathway. Altogether, our results suggest that LPS induces unbalanced proteostasis in astrocytes by blocking P2Y2 R. Finally, our findings point to the design of selective P2Y2 R agonist drugs as a new therapeutic approach to treat the neuroinflammatory status.-De Diego García, L., Sebastián-Serrano, Á., Hernández, I. H., Pintor, J., Lucas, J. J., Díaz-Hernández, M. The regulation of proteostasis in glial cells by nucleotide receptors is key in acute neuroinflammation.