Dysregulation of the SNARE-binding protein Munc18-1 impairs BDNF secretion and synaptic neurotransmission: a novel interventional target to protect the aging brain.

Autor: Lee YI; Department of Anatomy, College of Medicine, Dankook University, Cheonan, 330-714, South Korea., Kim YG; Department of Anatomy, College of Medicine, Dankook University, Cheonan, 330-714, South Korea.; Department of Nanobiomedical Science and WCU Research Center, Dankook University, Cheonan, 330-714, South Korea., Pyeon HJ; Department of Nanobiomedical Science and WCU Research Center, Dankook University, Cheonan, 330-714, South Korea.; Department of Anatomy and Cell Biology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea., Ahn JC; Department of Biomedical Science, Dankook University, Cheonan, 330-714, South Korea.; Biomedical Translational Research Institute, Dankook University, Cheonan, 330-714, South Korea., Logan S; Departments of Geriatric Medicine and Physiology, University Oklahoma HSC, Oklahoma City, OK, USA.; Reynolds Oklahoma Center on Aging, Oklahoma City, OK, USA.; Oklahoma Center for Neuroscience, Oklahoma City, OK, USA., Orock A; Departments of Geriatric Medicine and Physiology, University Oklahoma HSC, Oklahoma City, OK, USA.; Reynolds Oklahoma Center on Aging, Oklahoma City, OK, USA.; Oklahoma Center for Neuroscience, Oklahoma City, OK, USA., Joo KM; Department of Anatomy and Cell Biology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.; Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon, South Korea., Lőrincz A; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.; Florida State College at Jacksonville, 4500 Capper Rd, Jacksonville, FL, 32218, USA., Deák F; Departments of Geriatric Medicine and Physiology, University Oklahoma HSC, Oklahoma City, OK, USA. Ferenc-Deak@ouhsc.edu.; Reynolds Oklahoma Center on Aging, Oklahoma City, OK, USA. Ferenc-Deak@ouhsc.edu.; Oklahoma Center for Neuroscience, Oklahoma City, OK, USA. Ferenc-Deak@ouhsc.edu.; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA. Ferenc-Deak@ouhsc.edu.; Reynolds Oklahoma Center on Aging, Department of Geriatric Medicine, University of Oklahoma HSC, 975 N. E. 10th Street/SLY-BRC 1309-B, Oklahoma City, OK, 73104-5419, USA. Ferenc-Deak@ouhsc.edu.
Jazyk: angličtina
Zdroj: GeroScience [Geroscience] 2019 Apr; Vol. 41 (2), pp. 109-123. Date of Electronic Publication: 2019 Apr 30.
DOI: 10.1007/s11357-019-00067-1
Abstrakt: Brain-derived neurotrophic factor (BDNF) has a central role in maintaining and strengthening neuronal connections and to stimulate neurogenesis in the adult brain. Decreased levels of BDNF in the aging brain are thought to usher cognitive impairment. BDNF is stored in dense core vesicles and released through exocytosis from the neurites. The exact mechanism for the regulation of BDNF secretion is not well understood. Munc18-1 (STXBP1) was found to be essential for the exocytosis of synaptic vesicles, but its involvement in BDNF secretion is not known. Interestingly, neurons lacking munc18-1 undergo severe degeneration in knock-out mice. Here, we report the effects of BDNF treatment on the presynaptic terminal using munc18-1-deficient neurons. Reduced expression of munc18-1 in heterozygous (+/-) neurons diminishes synaptic transmitter release, as tested here on individual synaptic connections with FM1-43 fluorescence imaging. Transduction of cultured neurons with BDNF markedly increased BDNF secretion in wild-type but was less effective in munc18-1 +/- cells. In turn, BDNF enhanced synaptic functions and restored the severe synaptic dysfunction induced by munc18-1 deficiency. The role of munc18-1 in the synaptic effect of BDNF is highlighted by the finding that BDNF upregulated the expression of munc18-1 in neurons, consistent with enhanced synaptic functions. Accordingly, this is the first evidence showing the functional effect of BDNF in munc18-1 deficient synapses and about the direct role of munc18-1 in the regulation of BDNF secretion. We propose a molecular model of BDNF secretion and discuss its potential as therapeutic target to prevent cognitive decline in the elderly.
Databáze: MEDLINE
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