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

Lee, Youngil; Pyeon, Hee Jang; Ahn, Jin Ho; Logan, Sreemathi; Orock, Albert; Joo, Kyeung Min; Lőrincz, Andrea; Deák, F.

doi:10.1007/s11357-019-00067-1

Cited by 11 publications

(9 citation statements)

References 78 publications

(101 reference statements)

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“…Endocytosed BDNF is recycled for re-release event in neurons and astrocytes. ER endoplasmatic reticulum, IP3R inositol-3-phosphate receptor, NMDAR N-methyl d-aspartate receptor, TBS theta burst stimulation knockout mice heterozygous for munc-18, BDNF release is negatively affected (Lee et al 2019). The Ca 2+ -dependent activator protein for secretion (CAPS1) is another priming factor during exocytosis of synaptic vesicles and granule exocytosis in neurons (Farina et al 2015;Jockusch et al 2007).…”

Section: Contribution Of Regulatory Proteins and Snare Proteins To Bdmentioning

confidence: 99%

“…For BDNF-containing granules, some proteins and their binding partners have been identified. Among them are important cytosolic kinases (Gimenez-Cassina et al 2012 ; Gomes et al 2013 ; Hsieh et al 2010 ; Hutchinson et al 2009 ; Kolarow et al 2007 ; Santi et al 2006 ; Trang et al 2009 ), small G proteins (Hong et al 2016 ; Kato et al 2018 ; Persoon et al 2019 ), SNARE proteins (Dean et al 2009 ; Shimojo et al 2015 ; Wong et al 2015 ) and other priming factors (Eckenstaler et al 2016 ; Lee et al 2019 ).…”

Section: Molecular Mechanisms Underlying Release Of Bdnfmentioning

confidence: 99%

“…Therefore, Munc-18 is an essential protein for synaptic vesicle priming and stabilizing the core complex by binding to the SNARE protein syntaxin. Accordingly, in knockout mice heterozygous for munc-18, BDNF release is negatively affected (Lee et al 2019 ).…”

Section: Molecular Mechanisms Underlying Release Of Bdnfmentioning

confidence: 99%

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The physiology of regulated BDNF release

2020

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The neurotrophic factor BDNF is an important regulator for the development of brain circuits, for synaptic and neuronal network plasticity, as well as for neuroregeneration and neuroprotection. Up- and downregulations of BDNF levels in human blood and tissue are associated with, e.g., neurodegenerative, neurological, or even cardiovascular diseases. The changes in BDNF concentration are caused by altered dynamics in BDNF expression and release. To understand the relevance of major variations of BDNF levels, detailed knowledge regarding physiological and pathophysiological stimuli affecting intra- and extracellular BDNF concentration is important. Most work addressing the molecular and cellular regulation of BDNF expression and release have been performed in neuronal preparations. Therefore, this review will summarize the stimuli inducing release of BDNF, as well as molecular mechanisms regulating the efficacy of BDNF release, with a focus on cells originating from the brain. Further, we will discuss the current knowledge about the distinct stimuli eliciting regulated release of BDNF under physiological conditions.

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Section: Contribution Of Regulatory Proteins and Snare Proteins To Bdmentioning

confidence: 99%

Section: Molecular Mechanisms Underlying Release Of Bdnfmentioning

confidence: 99%

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The physiology of regulated BDNF release

2020

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“…Munc18-1 interacts with the SNARE complex [ 66 , 67 ] and facilitates the zippering of trans -SNARE complexes and promotes the SNARE-dependent membrane fusion in synaptosomes [ 68 ]. In contrast, knockdown of Munc18-1 shows abnormalities in cortical development [ 69 ] and diminished secretion of brain-derived neurotrophic factor [ 70 ]. In the present study, we observed Munc18-1 expression in the stratum lucidum in the hippocampus and its significant increase by entacapone treatment.…”

Section: Discussionmentioning

confidence: 99%

Entacapone Treatment Modulates Hippocampal Proteins Related to Synaptic Vehicle Trafficking

Yoo

Jung

Kim

et al. 2020

Cells

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Entacapone, a reversible inhibitor of catechol-O-methyl transferase, is used for patients in Parkinson’s disease because it increases the bioavailability and effectiveness of levodopa. In the present study, we observed that entacapone increases novel object recognition and neuroblasts in the hippocampus. In the present study, two-dimensional electrophoresis (2-DE) and matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry were performed to compare the abundance profiles of proteins expressed in the hippocampus after entacapone treatment in mice. Results of 2-DE, MALDI-TOF mass spectrometry, and subsequent proteomic analysis revealed an altered protein expression profile in the hippocampus after entacapone treatment. Based on proteomic analysis, 556 spots were paired during the image analysis of 2-DE gels and 76 proteins were significantly changed more than two-fold among identified proteins. Proteomic analysis indicated that treatment with entacapone induced expressional changes in proteins involved in synaptic transmission, cellular processes, cellular signaling, the regulation of cytoskeletal structure, energy metabolism, and various subcellular enzymatic reactions. In particular, entacapone significantly increased proteins related to synaptic trafficking and plasticity, such as dynamin 1, synapsin I, and Munc18-1. Immunohistochemical staining showed the localization of the proteins, and western blot confirmed the significant increases in dynamin I (203.5% of control) in the hippocampus as well as synapsin I (254.0% of control) and Munc18-1 (167.1% of control) in the synaptic vesicle fraction of hippocampus after entacapone treatment. These results suggest that entacapone can enhance hippocampal synaptic trafficking and plasticity against various neurological diseases related to hippocampal dysfunction.

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“…Munc18-1 can function to regulate brain-derived neurotrophic factors, participate in the development of synapses and affect cognitive functions ( 23 , 24 ). Synaptic plasticity is the basic process responsible for learning and memory ( 25 ).…”

Section: Function Of Munc18-1mentioning

confidence: 99%

Role of Munc18-1 in the biological functions and pathogenesis of neurological disorders (Review)

et al. 2021

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The release of neurotransmitters following the fusion of synaptic vesicles and the presynaptic membrane is an important process in the transmission of neuronal information. Syntaxin-binding protein 1 (Munc18-1) is a synaptic fusion protein binding protein, which mainly regulates synaptic vesicle fusion and neurotransmitter release by interacting with soluble n-ethylmaleimide sensitive factor attachment protein receptor. in addition to affecting neurotransmitter transmission, Munc18-1 is also involved in regulating neurosynaptic plasticity, neurodevelopment and neuroendocrine cell release functions (including thyroxine and insulin release). a number of previous studies have demonstrated that Munc18-1 has diverse and vital biological functions, and that its abnormal expression serves an important role in the pathogenesis of a variety of neurological diseases, including epileptic encephalopathy, schizophrenia, autism, Parkinson's disease, alzheimer's disease, multiple sclerosis, duchenne's muscular dystrophy and neuronal ceroid lipofuscinosis. The present review summarizes the function of Munc18-1 and its possible relationship to the pathogenesis of various neurological diseases. Contents 1. introduction 2. Function of Munc18-1 2. association between Munc18-1 and neurological disorders 3. conclusion and future perspectives

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

Cited by 11 publications

References 78 publications

The physiology of regulated BDNF release

The physiology of regulated BDNF release

Entacapone Treatment Modulates Hippocampal Proteins Related to Synaptic Vehicle Trafficking

Role of Munc18-1 in the biological functions and pathogenesis of neurological disorders (Review)

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