Synaptic Vesicle-Recycling Machinery Components as Potential Therapeutic Targets

Li, Ying C.; Kavalali, Ege T.

doi:10.1124/pr.116.013342

Cited by 60 publications

(59 citation statements)

References 349 publications

(337 reference statements)

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“…Stimulation at 10 Hz is believed to load FM1-43 into vesicles of both pools 44 , so our experiments should be labeling vesicles in the RRP and RP. Identifying where the problem is occurring may be challenging because there are many proteins involved in synaptic vesicle recycling 45 . Alterations to Ca 2+ levels could also be occurring, given the critical role of Ca 2+ has in endocytosis and exocytosis 46,47 .…”

Section: Discussionmentioning

confidence: 99%

The effect of NAMPT deletion in projection neurons on the function and structure of neuromuscular junction (NMJ) in mice

Lundt

Zhang

Wang

et al. 2020

Sci Rep

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Nicotinamide adenine dinucleotide (NAD +) plays a critical role in energy metabolism and bioenergetic homeostasis. Most NAD + in mammalian cells is synthesized via the NAD + salvage pathway, where nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme, converting nicotinamide into nicotinamide mononucleotide (NMN). Using a Thy1-Nampt −/− projection neuron conditional knockout (cKO) mouse, we studied the impact of NAMPT on synaptic vesicle cycling in the neuromuscular junction (NMJ), end-plate structure of NMJs and muscle contractility of semitendinosus muscles. Loss of NAMPT impaired synaptic vesicle endocytosis/exocytosis in the NMJs. The cKO mice also had motor endplates with significantly reduced area and thickness. When the cKO mice were treated with NMN, vesicle endocytosis/exocytosis was improved and endplate morphology was restored. Electrical stimulation induced muscle contraction was significantly impacted in the cKO mice in a frequency dependent manner. The cKO mice were unresponsive to high frequency stimulation (100 Hz), while the NMN-treated cKO mice responded similarly to the control mice. Transmission electron microscopy (TEM) revealed sarcomere misalignment and changes to mitochondrial morphology in the cKO mice, with NMN treatment restoring sarcomere alignment but not mitochondrial morphology. This study demonstrates that neuronal NAMPT is important for pre-/ post-synaptic NMJ function, and maintaining skeletal muscular function and structure. Nicotinamide adenine dinucleotide (NAD +) is found in all cells of the human body and is an important cofactor or co-substrate, used in numerous enzymatic processes including glycolysis, the tricarboxylic acid (TCA) cycle, oxidative phosphorylation, DNA repair, and protein deacetylation 1. NAD + levels may be important for many aspects of health and aging, including cellular metabolism, sarcopenia, and neurodegeneration 2. NAD + can be synthesized through multiple enzymatic pathways. One is a de novo pathway that begins with the amino acid tryptophan, while other pathways utilize different metabolites capable of being converted into NAD +. In mammalian cells, the majority of NAD + is produced from metabolites entering the NAD + salvage pathway 3. The rate limiting enzyme of the salvage pathway is nicotinamide phosphoribosyltransferase (NAMPT), which condenses nicotinamide (NAM) and 5-phosphoribosyl pyrophosphate (PRPP) into nicotinamide mononucleotide (NMN). NMN is subsequently synthesized into NAD + by nicotinamide mononucleotide adenylyltransferases (NMNATs) 4. NAD + levels decline with age and in different diseases. However, administration of NAD + precursor molecules, such as NMN or nicotinamide riboside (NR), are effective at preventing or reversing many age-or disease-related declines 5-10. NAD + and the NAD + salvage pathway are vitally important to maintain bioenergetic homeostasis, the normal health and function of many different organs and tissues in the human body, with neurons and skeletal muscles being impacted greatly. In n...

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Section: Discussionmentioning

confidence: 99%

The effect of NAMPT deletion in projection neurons on the function and structure of neuromuscular junction (NMJ) in mice

Lundt

Zhang

Wang

et al. 2020

Sci Rep

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“…Especially GABA agonists could be tested, which have shown positive effects on social deficits in ASD and are in clinical trials for Fragile-X syndrome (Erickson et al, 2017;Erickson et al, 2014a;Erickson et al, 2014b). Further development of drugs that target the presynapse and synaptic vesicle cycle could also be beneficial but are currently not well explored (Li and Kavalali, 2017).…”

Section: Cask-related Disorders Have Emerged As An Important Geneticmentioning

confidence: 99%

Presynaptic dysfunction inCASK-related neurodevelopmental disorders

Becker

Mastropasqua

Reising

et al. 2019

Preprint

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HighlightsModelling of CASK-related disorders using iPSC-derived human neuronal cells CASK mutations cause dysregulation of its protein interactor partners Reduced CASK levels primarily affect inhibitory presynapse development In vitro GABAergic phenotype predicts in vivo neurotransmitter levels Summary (150 words)CASK-related disorders are a genetically defined group of neurodevelopmental syndromes.There is limited information about the effects of CASK mutations in human neurons. Therefore, we sought to delineate CASK mutation consequences and neuronal level effects using induced pluripotent stem cell-derived neurons from two mutation carriers; one male diagnosed with ASD and a female with MICPCH. We show a reduction of the CASK protein in maturing neurons from the mutation carriers, which leads to significant downregulation of gene sets involved in presynaptic development and CASK protein interactors. Furthermore, CASKdeficient neurons showed decreased inhibitory presynapse size as indicated by VGAT staining, which may alter the excitatory-inhibitory (E/I) balance in developing neural circuitries. Using in vivo magnetic resonance spectroscopy quantification of GABA in the male mutation carrier, we further highlight the possibility to validate in vitro cellular data in brain. Our data shows that future pharmacological and clinical studies on targeting presynapses and E/I imbalance could lead to specific treatments for CASK-related disorders.

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“…Vesicles are docked to the internal presynaptic membrane, most commonly by synchronous fusion, an immensely complex process involving recruitment of a series of soluble N -ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins and binding partners, where docking is precisely time-locked to terminal depolarisation (Li 2017). Transmitter release, by a process called exocytosis, follows influx of calcium, with docked vesicles releasing their content into the synaptic cleft either through generation of a fusion pore or by complete membrane fusion and rupture (Fig.…”

Section: Management and Treatmentmentioning

confidence: 99%

“…The presynaptic membrane also contains pits coated with the protein clathrin, which provide a source of new vesicle formation. Although incredibly complex, the vesicular cycle, from budding to fusion/collapse, can be completed within a minute (Li 2017).…”

Section: Management and Treatmentmentioning

confidence: 99%

Tardive dyskinesia update: treatment and management

Owens¹

2018

BJPsych advances

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SUMMARYThe development of rational treatments for tardive dyskinesia has been held back by limitations to our understanding of its aetiology, which even now does not extend far beyond its association with centrally acting dopamine-blocking drugs. This article reviews briefly the major aetiological theories and addresses general management and specific treatment options. Primary prevention and early recognition remain the crucial management issues because, once the condition is established, there are no satisfactory treatments. The article considers two newly developed drugs, valbenazine and deutetrabenazine, in some detail as, although they are not yet licensed in Europe, they have largely been responsible for an upsurge in interest in tardive dyskinesia in the North American literature and are likely to be widely promoted in the future. Although possessed of undoubted benefits, the evidence suggests that these represent small steps rather than large leaps forward in treatment.LEARNING OBJECTIVES•Be able to discuss the major aetiological theories on the causation of a common, and sometimes serious, adverse action of antidopaminergic drugs•Understand general management and specific treatment options•Understand the pharmacology and efficacy of two drugs recently approved by the FDA for the treatment of tardive dyskinesiaDECLARATION OF INTERESTD.C.O. is psychiatric commissioner on the Commission on Human Medicines, the UK drug regulator, and chair of its expert advisory group on CNS drugs. He is also a member of the psychiatry Scientific Advisory Group of the European Medicines Agency.

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Synaptic Vesicle-Recycling Machinery Components as Potential Therapeutic Targets

Cited by 60 publications

References 349 publications

The effect of NAMPT deletion in projection neurons on the function and structure of neuromuscular junction (NMJ) in mice

The effect of NAMPT deletion in projection neurons on the function and structure of neuromuscular junction (NMJ) in mice

Presynaptic dysfunction inCASK-related neurodevelopmental disorders

Tardive dyskinesia update: treatment and management

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