Roles Of GPR50 In The Etiology Of Autism Spectrum Disorder Through Regulation Of Mitophagy

Autism spectrum disorder(ASD)is a complex neuronal developmental disorder and it is characterized by social interaction and communication difficulties as well as restricted or repetitive behavior.G protein-coupled receptor 50(GPR50)is an X-linked orphan G protein-coupled receptor,which is also known as melatonin-related receptor.GPR50 is mainly expressed in cell membrane of neuron.Interestingly,in male ASD patients,GPR50 have two variations,D502-505 and T532 A,suggesting a strong correlation between ASD and GPR50.However,it remains unclear that the function and molecular mechanism of GPR50 in ASD.In our study,we observe that GPR50 is recruited to mitochondria upon treatment with Carbonyl cyanide 3-chlorophenylhydrazone(CCCP)in He La cell.Furthermore,we are surprised to find that ectopically expressed GPR50 induced a significant increase of green fluorescent protein(GFP)–LC3 puncta,which are in close association with fragmented mitochondria,which is required for its binding to LC3.Our data indicate GPR50-/Y mice exhibit autism-like behaviors including impaired social interaction,stereotyped behavior and defective cognition.GPR50 knockout C57 mice exhibit elevated levels of ROS(reactive oxygen species)and deficits in social interaction and cognition,which is rescued by treatment with Mito-Q,an antioxidant.Together,these data provide evidence that GPR50,which is a novel mitophagy receptor,plays essential role in neurodevelopment through enhancing mitophagy.