Vesicular acetylcholine transporter defect underlies devastating congenital myasthenia syndrome

Aran, Adi; Segel, Reeval; Kaneshige, Kota; Gülsüner, Süleyman; Renbaum, Paul; Oliphant, Scott; Meirson, Tomer; Weinberg‐Shukron, Ariella; Hershkovitz, Yair; Zeligson, Sharon; Lee, Ming K.; Samson, Abraham O.; Parsons, Stanley M.; King, Mary Claire; Levy-Lahad, Ephrat; Walsh, Tom

doi:10.1212/wnl.0000000000003720

Cited by 27 publications

(39 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…; Aran et al . ) phenocopy mice with decreased levels of VAChT suggesting a high degree of functional conservation (Prado et al . ; Lima Rde et al .…”

Section: Discussionmentioning

confidence: 99%

Vesicular acetylcholine transporter (VAChT) over‐expression induces major modifications of striatal cholinergic interneuron morphology and function

Janickova

Prado

Mestikawy

et al. 2017

Journal of Neurochemistry

View full text Add to dashboard Cite

Striatal cholinergic interneurons (CIN) are pivotal for the regulation of the striatal network. Acetylcholine (ACh) released by CIN is centrally involved in reward behavior as well as locomotor or cognitive functions. Recently, BAC transgenic mice expressing channelrhodopsin-2 (ChR2) protein under the control of the choline acetyltransferase (ChAT) promoter (ChAT-ChR2) and displaying almost 50 extra copies of the VAChT gene were used to dissect cholinergic circuit connectivity and function using optogenetic approaches. These mice display over-expression of the vesicular acetylcholine transporter (VAChT) and increased cholinergic tone. Consequently, ChAT-ChR2 mice are a valuable model to investigate hypercholinergic phenotypes. Previous experiments established that ChAT-ChR2 mice display an increased sensitivity to amphetamine induced-locomotor activity and stereotypes. In the present report, we analyzed the impact of VAChT over-expression in the striatum of ChAT-ChR2 mice. ChAT-ChR2 mice displayed increased locomotor sensitization in response to low dose of cocaine. In addition, we observed a dramatic remodeling of the morphology of CIN in ChAT-ChR2 transgenic mice. VAChT immunolabeling was markedly enhanced in the soma and terminal of CIN from ChAT-ChR2 mice as previously shown (Crittenden et al. 2014). Interestingly, the number of cholinergic varicosities was markedly reduced (-87%) whereas their size was significantly increased (+177%). Moreover, VAChT over-expression dramatically modified its trafficking along the somatodendritic and axonal arbor. These findings demonstrate that ChAT-ChR2 mice present major alterations of CIN neuronal morphology and increased behavioral sensitization to cocaine, supporting the notion that the increased levels of VAChT observed in these mice make them fundamentally different from wild-type mice.

show abstract

“…; Aran et al . ) phenocopy mice with decreased levels of VAChT suggesting a high degree of functional conservation (Prado et al . ; Lima Rde et al .…”

Section: Discussionmentioning

confidence: 99%

Vesicular acetylcholine transporter (VAChT) over‐expression induces major modifications of striatal cholinergic interneuron morphology and function

Janickova

Prado

Mestikawy

et al. 2017

Journal of Neurochemistry

View full text Add to dashboard Cite

show abstract

“…Our group previously developed a mouse model with reduced expression of VAChT (VAChT KD HOM ) and found motor, 10,11 cardiac, 28 and synaptic 4,[8][9][10]12 alterations that resemble some of the features later discovered in CMS patients with mutations in VAChT. 6,7 Interestingly, adult animals already exhibit cognitive and behavioral impairment, with a 40% to 50% decrease in expression level of VAChT, 10 suggesting that central cholinergic synapses are even more sensitive to decreased VAChT activity than peripheral synapses, in which symptoms appear only after a 70% decrease in VAChT expression. 10 However, the possible effects of a long-term reduced ACh release at the neuromuscular junction have not yet been investigated.…”

Section: Discussionmentioning

confidence: 99%

“…5,6 Complete loss of function of VAChT disrupts the basis of cholinergic neurotransmission, leading to severe hypotonia and respiratory failure in humans. 7 In addition, VAChT knock-out (VAChT del/del ) mice die shortly after birth, indicating that VAChTmediated storage of ACh is essential for life and contributes to the normal development of the NMJ. 8 On the other hand, VAChT knock-down (VAChT KD HOM ) mice, which exhibit a 70% decrease in VAChT expression, are able to survive and reach adulthood, but they are myasthenic and have cognitive deficits.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the neuromuscular junction in a middle‐aged mouse model of congenital myasthenic syndrome

et al. 2019

View full text Add to dashboard Cite

Introduction Reduced expression of the vesicular acetylcholine transporter (VAChT) leads to changes in the distribution and shape of synaptic vesicles (SVs) at neuromuscular junctions (NMJs), suggesting vesicular acetylcholine (ACh) as a key component of synaptic structure and function. It is poorly understood how long‐term changes in cholinergic transmission contribute to age‐ and disease‐related degeneration in the motor system. Methods In this study we performed confocal imaging, electrophysiology, electron microscopy, and analyses of respiratory mechanics of the diaphragm NMJ components in 12‐month‐old wild‐type (WT) and VAChTKDHOM mice. Results Diaphragms of NMJs of the VAChTKDHOM mice were similar to those in WT mice in number, colocalization, and fragmentation of pre−/postsynaptic components. However, they had increased spontaneous SV exocytosis, miniature endplate potential frequency, and diminished MEPP amplitude. No impairment in respiratory mechanics at rest was observed, probably due to the large neurotransmission safety factor of the diaphragm. Discussion The present findings help us to understand the consequences of reduced ACh release at the NMJs during aging.

show abstract

“…SLC18A3 (solute carrier family 18 member A3; MIM 600336) encodes vesicular acetylcholine transporter (VAChT), which packages acetylcholine into presynaptic vesicles 47. Biallelic mutations cause presynaptic CMS, with severe presentations including fetal akinesia 47.…”

Section: Genes Encoding Components Of the Nmjmentioning

confidence: 99%

“…Biallelic mutations cause presynaptic CMS, with severe presentations including fetal akinesia 47. Aran et al described two brothers with retrognathia, severe hypotonia, bilateral dislocated hips, bilateral undescended testes, micropenis and marked hirsutism.…”

Section: Genes Encoding Components Of the Nmjmentioning

confidence: 99%

Genetics of neuromuscular fetal akinesia in the genomics era

et al. 2018

View full text Add to dashboard Cite

Fetal hypokinesia or akinesia encompasses a broad spectrum of disorders, united by impaired movement in utero. Often, the underlying aetiology is genetic in origin, affecting part of the neuromuscular system. The affordable and high-throughput nature of next-generation DNA sequencing has led to an explosion in disease gene discovery across rare diseases, including fetal akinesias. A genetic diagnosis has clinical utility as it may affect management and prognosis and informs recurrence risk, facilitating family planning decisions. More broadly, knowledge of disease genes increasingly allows population-based preconception carrier screening, which has reduced the incidence of recessive diseases in several populations. Despite gains in knowledge of the genetics of fetal akinesia, many families lack a genetic diagnosis. In this review, we describe the developments in Mendelian genetics of neuromuscular fetal akinesia in the genomics era. We examine genetic diagnoses with neuromuscular causes, specifically including the lower motor neuron, peripheral nerve, neuromuscular junction and muscle.

show abstract

Vesicular acetylcholine transporter defect underlies devastating congenital myasthenia syndrome

Abstract: Loss of function of VAChT underlies severe arthrogryposis and respiratory failure. While most congenital myasthenic syndromes are caused by defects in postsynaptic proteins, VAChT deficiency is a presynaptic myasthenic syndrome.

Cited by 27 publications

References 33 publications

Vesicular acetylcholine transporter (VAChT) over‐expression induces major modifications of striatal cholinergic interneuron morphology and function

Vesicular acetylcholine transporter (VAChT) over‐expression induces major modifications of striatal cholinergic interneuron morphology and function

Evaluation of the neuromuscular junction in a middle‐aged mouse model of congenital myasthenic syndrome

Genetics of neuromuscular fetal akinesia in the genomics era

Contact Info

Product

Resources

About