MicroRNA-26a/Death-associated Protein Kinase 1 Signaling Induces Synucleinopathy And Dopaminergic Neuron Degeneration In Parkinson's Disease

Background: Death-associated protein kinase 1(DAPK1)is a widely distributed serine/threonine(Ser/Thr)kinase that is critical for cell death in multiple neurological disorders,including Alzheimer's disease(AD)and stroke.However,little is known about the role of DAPK1 in the pathogenesis of Parkinson's disease(PD),the second most common neurodegenerative disorder.Aim: To explore the role of DAPK1 in the pathogenesis of Parkinson's disease.Methods: Parkinson's disease model mice were induced by injection of MPTP.We use western blot,immunohistochemistry to evaluate the alteration of DAPK1.Q-PCR and FISH were used to analyze the expression of mi RNAs.Rotarod,open field and pole tests were used to evaluate the locomotor ability.Virus were used to regulate the expression of DAPK1 in vivo.Immunofluorescence,western blot and filter trap were used to evaluate synucleinopathy.Genetic deletion of DAPK1 in DA neurons by crossing the DAT-Cre mice with DAPK1 floxed mice.A cell-permeable competing peptide was used to research the potential strategy.Results: We find that DAPK1 is post-transcriptionally upregulated by a reduction in mi R-26 a caused by a loss of the C/EBPa transcription factor.The overexpression of DAPK1 in PD mice is positively correlated with neuronal synucleinopathy.Suppressing mi R-26 a or upregulating DAPK1 results in synucleinopathy,DA neuron cell death and motor disabilities in wild-type(wt)mice.In contrast,genetic deletion of DAPK1 in DA neurons by crossing the DAT-Cre mice with DAPK1 floxed mice effectively rescues the abnormalities in mice with chronic MPTP treatment.We further show that DAPK1 overexpression promotes PD-like phenotypes by direct phosphorylation of a-synuclein at Ser129 site.In line with this,a cell-permeable competing peptide that blocks the phosphorylation of a-synuclein prevents motor disorders,synucleiopathy and dopaminergic neuron loss in the MPTP mice.Conclusions: We conclude that mi R-26a/DAPK1 signaling cascades are essential in the formation of the molecular and cellular pathologies in PD.