Preliminary Study On The Regulation Of ER-phagy By BPAN Pathogenic Gene WDR45 Knockout Mice

?-propeller Protein Associated Neurodegeneration(BPAN)is a subtype of NBIA(Neurodegeneration with Brain Iron Accumulation),characterized by a biphasic clinical manifestation.In childhood,it is characterized by global developmental delay,autism and epilepsy.While in adulthood,it is characterized by progressive cognitive impairment and parkinsonism.In 2012,mutation in WDR45 was found to be responsible for BPAN by exon sequencing.Previous studies by Hong Zhang found that neuronal specific knockout of Wdr45 in mice(cKO)resulted in a significant impairment of learning and cognition.Our study at the cellular level showed that knocking out WDR45 resulted in abnormally expanded endoplasmic reticulum tubule.However,the specific mechanism of WDR45 in regulation of endoplasmic reticulum autophagy is still unclear.This study,on the one hand examined ASD-related behavioral and pilocarpine-induced epilepsy in KO mouse;on the other hand,performed proteomic analysis on enriched endoplasmic reticulum fractions in mouse prefrontal cortex(PFC)to identify potential targets involved in WDR45 regulation of ER-phagy.The results showed that WDR45-deficient mice displayed autistic behaviors,a significantly shorter latency of highest grade seizure and increased seizure severity compared to the WT mice.Mass spectrometry revealed a significantly higher expression of RTN3,a known ER-phagy receptor.These findings suggest that Wdr45 knockout mice can model a subset of BPAN behaviors,and provide starting point to understand the mechanism of WDR45 regulation of ER-phagy.