The Role Of Ubiquitin Specific Protease USP25 In The Pathogenesis Of Down Syndrome

Down syndrome(DS)is the most common genetic cause of intellectual disability,an additional copy of human chromosome 21 causes most DS cases.DS patients inevitably develop typical pathology of Alzheimer’s disease(AD),which is the most common neurodegenerative disease characterized by extracellular amyloid plaque deposition,intracellular neurofibrillary tangles and neuron loss.Pathological manifestations include intellectual disability and cognitive impairment.Ubiquitin-specific protease 25(USP25)is a deubiquitinase located in the critical region of DS on human chromosome 21.It is highly expressed in DS patients and has been proved to be involved in a variety of cellular processes,including immunity,myogenesis and protein degradation.However,the potential role of USP25 in DS pathogenesis is still not clear.The purpose of this study was to investigate the role of USP25 in DS pathogenesis.First,we found that USP25 was highly expressed in DS human brain and a widely used DS mouse model(Dp 16),suggesting that USP25 may play a potential role in DS pathogenesis.In addition,we found enlarged size of mitochondria in both cerebral cortex and hippocampus of Usp25 knockout mice.Consistently,the oxidative respiratory function of mitochondria is enhanced upon Usp25 deletion,suggesting a possibility to rescue the mitochondrial dysfunction of DS neurons through targeting USP25.Therefore,we crossed Usp25 knockout with Dp 16 mice to generate Usp25+/-;Dp16 mice.Interestingly,Usp25 deletion restores both morphological and functional defects of DS mitochondria in Usp25+/-;Dp16 mice,and the cognitive impairment of Dp16 mice was also reversed upon USP25 deletion.Consistently,we performed RNA-seq analysis of Usp25+/.;Dp16 mouse brains and identified that mitochondrial-related pathways rank the top regulated pathways.In conclusion,this study determined the role of Usp25 in DS pathogenesis.Overdosage of USP25 plays an important role in neuronal deficits of DS through disrupting mitochondrial function.Deletion of Usp25 gene restored cognitive function of DS mice.These results suggest that targeting USP25 may bring a potential for the treatment of DS.