SNAREopathies: Diversity in Mechanisms and Symptoms

Verhage, Matthijs; Sørensen, Jakob Balslev

doi:10.1016/j.neuron.2020.05.036

Cited by 89 publications

(120 citation statements)

References 137 publications

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“…Our results are in agreement with recent in vitro studies showing that DAP also can overcome release deficits associated with disease‐causing synaptotagmin‐1 variants (Bradberry et al, 2020). Taken together, these observations confirm and expand our hypothesis that augmentation of release by DAP or 4‐AP would be a viable treatment option for other SNAREopathies as well (Baker et al, 2018; Harper, Mancini, van Slegtenhorst, & Cousin, 2017; Salpietro et al, 2017; Verhage & Sorensen, 2020). This approach could be tested in vitro before clinical implementation.…”

Section: Discussionsupporting

confidence: 81%

“…Taken together, these observations confirm and expand our hypothesis that augmentation of release by DAP or 4-AP would be a viable treatment option for other SNAREopathies as well (Baker et al, 2018;Harper, Mancini, van Slegtenhorst, & Cousin, 2017;Salpietro et al, 2017;Verhage & Sorensen, 2020). This approach could be tested in vitro before clinical implementation.…”

Section: Discussionsupporting

confidence: 80%

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Overcoming presynaptic effects of VAMP2 mutations with 4‐aminopyridine treatment

Simmons

Alten

et al. 2020

Human Mutation

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Clinical and genetic features of five unrelated patients with de novo pathogenic variants in the synaptic vesicle-associated membrane protein 2 (VAMP2) reveal common features of global developmental delay, autistic tendencies, behavioral disturbances, and a higher propensity to develop epilepsy. For one patient, a cognitively impaired adolescent with a de novo stop-gain VAMP2 mutation, we tested a potential treatment strategy, enhancing neurotransmission by prolonging action potentials with the aminopyridine family of potassium channel blockers, 4-aminopyridine and 3,4-diaminopyridine, in vitro and in vivo. Synaptic vesicle recycling and neurotransmission were assayed in neurons expressing three VAMP2 variants by live-cell imaging and electrophysiology. In cellular models, two variants decrease both the rate of exocytosis and the number of synaptic vesicles released from the recycling pool, compared with wild-type. Aminopyridine treatment increases the rate and extent of exocytosis and total synaptic charge transfer and desynchronizes GABA release. The clinical response of the patient to 2 years of

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Section: Discussionsupporting

confidence: 81%

Section: Discussionsupporting

confidence: 80%

Overcoming presynaptic effects of VAMP2 mutations with 4‐aminopyridine treatment

Simmons

Alten

et al. 2020

Human Mutation

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“…The synaptic exocytic SNAREs have known roles in key processes of neural development, such as axon guidance (Barrecheguren et al, 2017; Cotrufo et al, 2011; Ros et al, 2018). Unsurprisingly, therefore, genetic mutations or variants of these SNAREs and their interacting partners of the synaptic exocytic machinery, particularly, give rise to an array of neurological manifestations in humans and mice (Cupertino et al, 2016; Verhage & Sørensen, 2020). These are broadly summarized in Table 1, and shall be considered below.…”

Section: Neurodevelopmental Disorders Associated With the Canonical Smentioning

confidence: 99%

“…Neurological disorders, or SNAREopathies (Verhage & Sørensen, 2020), that are associated with MUNC18‐1 have in fact been much more widely identified compared to its SNARE partners. Early analysis the Drosophila MUNC18‐1 orthologue Rop showed that null mutants die at a late embryonic stage (Harrison et al, 1994) and various Rop mutation affect neurotransmission (M. N. Wu et al, 1998).…”

Section: Neurodevelopmental Disorders Associated With the Canonical Smentioning

confidence: 99%

SNAREs and developmental disorders

Tang

2020

Journal Cellular Physiology

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Members of the soluble N‐ethylmaleimide‐sensitive factor attachment protein receptor (SNARE) family mediate membrane fusion processes associated with vesicular trafficking and autophagy. SNAREs mediate core membrane fusion processes essential for all cells, but some SNAREs serve cell/tissue type‐specific exocytic/endocytic functions, and are therefore critical for various aspects of embryonic development. Mutations or variants of their encoding genes could give rise to developmental disorders, such as those affecting the nervous system and immune system in humans. Mutations to components in the canonical synaptic vesicle fusion SNARE complex (VAMP2, STX1A/B, and SNAP25) and a key regulator of SNARE complex formation MUNC18‐1, produce variant phenotypes of autism, intellectual disability, movement disorders, and epilepsy. STX11 and MUNC18‐2 mutations underlie 2 subtypes of familial hemophagocytic lymphohistiocytosis. STX3 mutations contribute to variant microvillus inclusion disease. Chromosomal microdeletions involving STX16 play a role in pseudohypoparathyroidism type IB associated with abnormal imprinting of the GNAS complex locus. In this short review, I discuss these and other SNARE gene mutations and variants that are known to be associated with a variety developmental disorders, with a focus on their underlying cellular and molecular pathological basis deciphered through disease modeling. Possible pathogenic potentials of other SNAREs whose variants could be disease predisposing are also speculated upon.

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“…SNARE proteins are generally small proteins of around 100–300 aminoacids and they mediate the fusion of biological membranes by localizing both at the vesicular membrane and on the target membrane (for further details please refer to [ 23 , 24 , 25 , 26 , 27 ]. They share a common domain, the SNARE motif, which is normally of 60 aa in length.…”

Section: Introductionmentioning

confidence: 99%

Role of SNAREs in Neurodegenerative Diseases

Margiotta

2021

Cells

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Neurodegenerative diseases are pathologies of the central and peripheral nervous systems characterized by loss of brain functions and problems in movement which occur due to the slow and progressive degeneration of cellular elements. Several neurodegenerative diseases are known such as Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis and many studies on the molecular mechanisms underlying these pathologies have been conducted. Altered functions of some key proteins and the presence of intraneuronal aggregates have been identified as responsible for the development of the diseases. Interestingly, the formation of the SNARE complex has been discovered to be fundamental for vesicle fusion, vesicle recycling and neurotransmitter release. Indeed, inhibition of the formation of the SNARE complex, defects in the SNARE-dependent exocytosis and altered regulation of SNARE-mediated vesicle fusion have been associated with neurodegeneration. In this review, the biological aspects of neurodegenerative diseases and the role of SNARE proteins in relation to the onset of these pathologies are described.

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SNAREopathies: Diversity in Mechanisms and Symptoms

Cited by 89 publications

References 137 publications

Overcoming presynaptic effects of VAMP2 mutations with 4‐aminopyridine treatment

Overcoming presynaptic effects of VAMP2 mutations with 4‐aminopyridine treatment

SNAREs and developmental disorders

Role of SNAREs in Neurodegenerative Diseases

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