The role of ubiquilin in AMPA receptor ubiquitination and proteasomal degradation
Ubiquilin (UBQLN) is a member of type2 ubiquitin-like (UBL) protein family characterized by an UBL domain at the N-terminus and an ubiquitin associated (UBA) domain at the C-terminus. This protein has been shown to play an important role in the regulation of the levels, aggregation and degradation of various neurodegenerative disease-associated proteins. However, the specific functions and mechanisms of UBQLN regulation still remain to be elucidated. In this study, we investigate the effect of UBQLN expression on α-Amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid receptor (AMPAR) degradation and the underlying molecular mechanisms. We show that UBQLN overexpression decreases AMPAR levels in neurons and also reduces GluA1 expression in HEK 293T cells. Moreover, our results indicate that UBQLN can form a complex with GluA1, and this interaction is related to the ubiquitination of AMPARs. In addition, we find a higher expression of UBQLN2 in Alzheimer’s disease (AD) patient brains, which might be a potential pathological mechanism of GluA1 reduction in AD. Given the crucial effect of UBQLN in AMPAR regulation, UBQLN may play an important role in synaptic transmission, brain functions as well as neurodegenerative diseases.