Presenilin2 D439A mutation induced the dysfunction of mitochondrial fusion/fission dynamics via regulating Miro2 in Alzheimer’s disease

Abstract Alzheimer's disease (AD) is an age-related progressive neurodegenerative disease, about 10% of AD patients are called early-onset familial AD (EOFAD), which is mainly linked to the point mutations in genes encoding Presenilins ( PS1 and PS2 ). Mutations in PS2 are extremely rare and PS2 mutations have not received enough attention. Recently studies have found that Rho GTPase was closely related to the pathogenesis of AD. In this study, we used transcriptome sequencing in PS2 siRNA SH-SY5Y cells and found a group of differential expression genes (DEGs) play a key role in the regulation of GTPase activity. Among those DEGs, the most significantly down regulated was Rho guanine nucleotide exchange factor5 (ARHGEF5). The GTPase activity in PS2 siRNA cells decreased significantly. Then we found that the expression of ARHGEF5 and the GTPase activity of Mitochondrial Rho GTPase 2 (Miro2) in PS2 D439A mutant SH-SY5Y cells decreased significantly. We found for the first time that PS2 can bind to Miro2, and PS2 D439A mutation reduced the binding between PS2 and Miro2, reduced the expression of Miro2, and resulted in the imbalance of mitochondrial fusion/fission dynamics. In conclusion, PS2 gene knockdown may participate in the pathogenesis of AD through the regulation of GTPase activity. The imbalance of mitochondrial dynamics mediated by PS2 D439A mutation through regulating Miro2 expression and Miro2-GTPase activity may be one of the potential pathogenic mechanisms of AD.