2. Academic Validation
  3. MicroRNA-26a/Death-Associated Protein Kinase 1 Signaling Induces Synucleinopathy and Dopaminergic Neuron Degeneration in Parkinson's Disease

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

  • Biol Psychiatry. 2019 May 1;85(9):769-781. doi: 10.1016/j.biopsych.2018.12.008.
Ying Su 1,  Man-Fei Deng 2,  Wan Xiong 2,  Ao-Ji Xie 2,  Jifeng Guo 3,  Zhi-Hou Liang 4,  Bo Hu 4,  Jian-Guo Chen 5,  Xiongwei Zhu 6,  Heng-Ye Man 7,  Youming Lu 5,  Dan Liu 8,  Beisha Tang 9,  Ling-Qiang Zhu 10
Affiliations

Affiliations

  • 1 Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Institute of Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, China.
  • 2 Department of Pathophysiology, Key Lab of Neurological Disorder of Education Ministry, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Institute of Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, China.
  • 3 National Research Center for Geriatric Diseases, Xiangya Hospital, and Center for Medical Genetics, School of Life Science, Central South University, Changsha, Hunan, China.
  • 4 Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 5 Institute of Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, China.
  • 6 Department of Pathology, Case Western Reserve University, Cleveland, Ohio.
  • 7 Department of Biology, Boston University, Boston, Massachusetts.
  • 8 Department of Medical Genetics, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Institute of Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, China.
  • 9 National Research Center for Geriatric Diseases, Xiangya Hospital, and Center for Medical Genetics, School of Life Science, Central South University, Changsha, Hunan, China. Electronic address: [email protected].
  • 10 Department of Pathophysiology, Key Lab of Neurological Disorder of Education Ministry, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Institute of Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, China; National Research Center for Geriatric Diseases, Xiangya Hospital, and Center for Medical Genetics, School of Life Science, Central South University, Changsha, Hunan, China. Electronic address: [email protected].
PMID: 30718039 DOI: 10.1016/j.biopsych.2018.12.008
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 α-synuclein at the serine 129 site. Correspondingly, a cell-permeable competing peptide that blocks the phosphorylation of α-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.

Keywords

DAPK1; MPTP; Parkinson’s disease; Peptide; miRNA; α-Synuclein.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
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  • HY-15513
    98.26%, DAPK Inhibitor