MicroRNA-26a/Death-Associated Protein Kinase 1 Signaling Induces Synucleinopathy and Dopaminergic Neuron Degeneration in Parkinson’s Disease

Abstract

BACKGROUND: Death-associated protein kinase 1 (DAPK1) is a widely distributed serine/threonine kinase that is critical for cell death in multiple neurological disorders, including Alzheimer's disease 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. METHODS: We used Western blot and immunohistochemistry to evaluate the alteration of DAPK1. Quantitative polymerase chain reaction and fluorescence in situ hybridization were used to analyze the expression of microRNAs in PD mice and patients with PD. Rotarod, open field, and pole tests were used to evaluate the locomotor ability. Immunofluorescence, Western blot, and filter traps were used to evaluate synucleinopathy in PD mice. RESULTS: We found that DAPK1 is posttranscriptionally upregulated by a reduction in microRNA-26a (miR-26a) caused by a loss of the transcription factor CCAAT enhancer-binding protein alpha. The overexpression of DAPK1 in PD mice is positively correlated with neuronal synucleinopathy. Suppressing miR-26a or upregulating DAPK1 results in synucleinopathy, dopaminergic neuron cell death, and motor disabilities in wild-type mice. In contrast, genetic deletion of DAPK1 in dopaminergic neurons by crossing DAT-Cre mice with DAPK1 floxed mice effectively rescues the abnormalities in mice with chronic MPTP treatment. We further showed that DAPK1 overexpression promotes PD-like phenotypes by direct phosphorylation of a-synuclein at the serine 129 site. Correspondingly, a cell-permeable competing peptide that blocks the phosphorylation of a-synuclein prevents motor disorders, synucleinopathy, and dopaminergic neuron loss in the MPTP mice. CONCLUSIONS: miR-26a/DAPK1 signaling cascades are essential in the formation of the molecular and cellular pathologies in PD.

LncRNA MALAT1 targeting miR‐124‐3p regulates DAPK1 expression contributes to cell apoptosis in Parkinson's Disease

“…28 DAPK1 expression is markedly raised in MPTP-induced chronic and acute PD mice, while the DAPK1 protein levels are suppressed by miR-26a overexpression. 10 However, the mechanisms between DAPK1 and noncoding RNAs are still not unclear. Therefore, we first picked out targeting DAPK1 miRNAs through TargetScan and miRNA.org, and further RT-PCR data indicated miR-124-3p was the optimal candidate.…”

“…9 Furthermore, active DAPK1 promotes α-synuclein phosphorylation, overexpression of DAPK1 results in dopaminergic neuron injury and locomotor disabilities in mice with Parkinson's disease. 10 Although the previous studies indicated that the abnormal expression of DAPK1 plays a key role in central nervous system disorders, the underlying mechanisms remain unclear.…”

“…13 Similarly, miR-26a also negatively regulates DAPK1 and mediated neuron apoptosis in ischemia/reperfusion injury and PD. 8,10 Particularly, these reports revealed that miRNAs interact with DAPK1 in PD, the potential mechanisms have not yet been elucidated completely.…”

MiR‐21‐5p/dual‐specificity phosphatase 8 signalling mediates the anti‐inflammatory effect of haem oxygenase‐1 in aged intracerebral haemorrhage rats

“…An increasing number of miRNAs have emerged as biomarkers for the diagnosis and prognosis of various neurological diseases (Wang et al, ; Xie et al, ). Accumulating data imply that differential miRNA expression profiles detected by sequencing are involved in developing cognitive defects (Tang et al, ) and Parkinson's disease (Su et al, ). In this study, we identified that miR‐21‐5p mediated haemin neuroprotection by targeting DUSP8 to alleviate neuroinflammation.…”

Haplopelma hainanum venom induces inflammatory skin lesions

“…The ears were sectioned at 8 µm thickness and incubated with anti-CD4, anti-CD31, and anti-MHCII antibodies (4 ears per group), and then stained with anti-goat IgG antibodies (Alexa Fluor 488) as previously described (Su et al, 2018). All antibodies were purchased from ebioscience (San Diego, USA).…”