MTMR14 Promotes Tau Accumulation Via Inhibiting Autophagy

【Background】 Alzheimer’s disease(AD)is currently the most common neurodegenerative disease,mainly responsible for progressive learning and memory impairment.AD is characterized by the presence of extracellular Aβ plaques and intracellular neurofibrillary tangles formed by hyperphosphorylated tau accumulation.Autophagy is a process that maintains homeostasis by degrading cytoplasmic materials,including misfolded proteins and damaged organelles.Increasing studies have shown that autophagy plays a significant role in the pathogenesis of cancer,neurodegenerative diseases,muscle diseases,infectious diseases and immune system diseases.【Objective】 To explore the role and mechanism of MTMR14 in promoting tau accumulation.【Methods】 In cerebral cortex of Tau-P301 S transgenic mice(9-month-old),the MTMR14 and autophagy marker LC3 and P62 protein levels were detected by western blots.Primary neurons were exposed to Aβ and the levels of MTMR14 were detected by western blots.HEK293 cells were transfected with p EGFP-C1-Tau-P301 S or p EGFP-C1-MTMR14 plasmids and its empty vector,and then,MTMR14,LC3 II and P62 levels were measured by western blots.HEK293 cells were co-transfected with p EGFP-C1-Tau-P301 S and p EGFP-C1-MTMR14 plasmids,and then,total and phosphorylated tau levels were measured by western blots.HEK293 cells were co-transfected with m Cherry-LC3 and p EGFP-C1-Tau-P301 S or p EGFP-C1-MTMR14 plasmids,and the LC3 puncta was measured by direct fluorescence imaging.HEK293 cells were co-transfected with p EGFP-C1-MTMR14 and Ds Red-mito plasmids,and then the locations of MTMR14 and mitochondria was detected by direct fluorescence imaging.【Results】 1.The levels of MTMR14 and autophagy markers LC3 II and P62 in the cortex of Tau-P301 S transgenic mice(9-month-old)increased.2.Overexpression of Tau-P301 S in HEK293 cells significantly increased MTMR14 protein level and the number of LC3 puncta.3.Aβ exposure significantly increased the levels of MTMR14 in primary neurons.4.Overexpression of MTMR14 in HEK293 cells significantly increased the levels of LC3 II and P62 and the number of LC3 II puncta.5.Co-overexpression of Tau-P301 S and MTMR14 in HEK293 cells significantly increased the levels of total tau and phosphorylated tau.6.MTMR14 localizes in the mitochondria.【Conclusion】 Tau/Aβ induces MTMR14 protein levels increase,and MTMR14 can localize in the mitochondria and cause autophagy deficits.Elevated MTMR14 damaged autophagy,and further lead to impair tau clearance,which lead to tau accumulation.