VU Research Portal SNAREopathies Verhage, Matthijs; Sørensen, Jakob B. published in Neuron 2020 DOI (link to publisher) 10.1016/j.neuron.2020.05.036 document version Publisher's PDF, also known as Version of record document license Article 25fa Dutch Copyright Act Link to publication in VU Research Portal citation for published version (APA) Verhage, M., & Sørensen, J. B. (2020). SNAREopathies: Diversity in Mechanisms and Symptoms. Neuron, 107(1), 22-37. https://doi.org/10.1016/j.neuron.2020.05.036 General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal ? Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. E-mail address: [email protected] Download date: 29. Sep. 2021 ll Review SNAREopathies: Diversity in Mechanisms and Symptoms Matthijs Verhage1,2,* and Jakob B. Sørensen3,* 1Department of Functional Genomics, Vrije Universiteit (VU) Amsterdam, De Boelelaan 1085, Amsterdam 1081 HV, the Netherlands 2Department of Clinical Genetics, UMC Amsterdam, De Boelelaan 1085, Amsterdam 1081 HV, the Netherlands 3Department of Neuroscience, University of Copenhagen, 2200 Copenhagen N, Denmark *Correspondence: [email protected] (M.V.), [email protected] (J.B.S.) https://doi.org/10.1016/j.neuron.2020.05.036 Neuronal SNAREs and their key regulators together drive synaptic vesicle exocytosis and synaptic transmis- sion as a single integrated membrane fusion machine. Human pathogenic mutations have now been reported for all eight core components, but patients are diagnosed with very different neurodevelopmental syn- dromes. We propose to unify these syndromes, based on etiology and mechanism, as ‘‘SNAREopathies.’’ Here, we review the strikingly diverse clinical phenomenology and disease severity and the also remarkably diverse genetic mechanisms. We argue that disease severity generally scales with functional redundancy and, conversely, that the large effect of mutations in some SNARE genes is the price paid for extensive inte- gration and exceptional specialization. Finally, we discuss how subtle differences in components being rate limiting in different types of neurons helps to explain the main symptoms. Twenty-five years after their discovery (Schiavo et al., 1995; So¨ ll- guage, motor function, and intellectual ability, as the most com- ner et al., 1993), the evidence of a crucial role of SNARE (soluble mon aspect. In addition, other neurological features associated NSF attachment protein receptor) complexes in many mem- with severe developmental delay are observed, such as seizures brane fusion processes in the brain is overwhelming (Sudhof€ and epileptiform abnormalities, and neurological motor prob- and Rothman, 2009). The neuronal SNAREs syntaxin 1, lems, such as spasms and ataxia (Figure 2; Table 1). Children SNAP25, and synaptobrevin/VAMP2 are at the core of a highly carrying mutations in a single SNAREopathy gene can conserved, integrated molecular machine that drives synaptic have more than 10 different diagnoses, depending on how transmission by synaptic vesicle exocytosis (Sudhof€ and Roth- they entered the health care system (https://stxbp1.cncr.nl/ man, 2009) and also secretion of neuropeptides and neurotro- stxbp1_disorders), a situation referred to as ‘‘the diagnostic od- phins from dense core vesicles (Arora et al., 2017; Shimojo yssey’’ for the families and caretakers. Hence, despite strong ev- et al., 2015). Strikingly, there is no backup plan for these fusion idence that these proteins work together in a well-integrated mo- reactions. Inactivation of single SNARE genes or the SNARE lecular machine, mutations in individual components produce a organizer MUNC18-1 abolishes synaptic transmission and surprisingly diverse collection of symptoms and diverse di- even prevents spontaneous fusion events in most neurons stud- agnoses. ied so far (Schoch et al., 2001; Verhage et al., 2000; Washbourne The diversity of symptoms among cases and also differences et al., 2002). Given this lack of redundancy, mutations in the hu- in severity resembles the clinical picture observed for carriers of man genes encoding these proteins are expected to result in mutations in another class of functionally related proteins: the clinically important effects on brain function. In 2008, the first hu- voltage-gated K+,Na+, and Ca2+ channels, together referred to man patients were described, initially with mutations in STXBP1 as ‘‘channelopathies’’ (Kullmann, 2010). We propose to consider (Saitsu et al., 2008), the human gene encoding MUNC18-1. To disorders emerging from mutations in the functionally related date, patients have been described carrying mutations in each SNARE machinery ‘‘SNAREopathies’’—a subset of the previ- neuronal SNARE gene and in five genes encoding important or- ously defined synaptopathies (Grant, 2012). However, the latter ganizers of neuronal SNARE function that together constitute the comprise a much more diverse group of genes; e.g., localized integrated molecular fusion machine (Figure 1; Table 1). Most re- to different compartments (pre- and postsynaptic) and with ported mutations are heterozygous de novo missense or loss-of- diverse molecular functions. We define a SNAREopathy as a function (LoF) mutations (mutations that result in reduced or brain disease caused by mutations that disturb synaptic SNARE abolished protein function: [partial] gene deletions, small inser- function; i.e., including disturbed functions of key regulators of tions, truncations, and frameshift or splice-site mutations). The SNARE function (Table 1; together referred to as ‘‘SNAREopathy causality of these mutations is now fairly well established, at genes’’; Figure 1). Such a functional classification provides key least in a few of these genes. It could be expected that mutations advantages to (1) delineate a clinical subgroup with a common in any component of this integrated machine lead to similar pathogenic starting point, (2) end the diagnostic odyssey for pa- symptoms. However, recent studies now suggest that mutations tient families, (3) contribute to elucidation of pathogenic path- give rise to a surprisingly diverse palette of symptoms, with neu- ways toward clinical neurodevelopmental phenotypes, and (4) rodevelopmental delay (NDD) in the domains of speech, lan- eventually develop intervention strategies. The aim of this review 22 Neuron 107, July 8, 2020 ª 2020 Elsevier Inc. ll Review Figure 1. Schematic Representation of the Eight SNAREopathy Genes with Their Orientation Relative to the Synaptic Vesicle (Gray Circle) and the Plasma Membrane (Gray Line), Their Main Protein Domains, and Their Main Interactions SNARE domains are depicted as aligned ellipses in the center. Indicated names are commonly used protein names followed by the official gene names separated by a comma. Firm evidence that mutations in a given gene specifically disturb synaptic SNARE function was taken as the main inclusion criterion for SNARE- opathy genes. Hence, although only three of these eight SNAREopathy genes are SNAREs, all of them together serve a single purpose (SNARE-mediated membrane fusion), and mutations in any of these eight are expected to lead to a single convergent defect (dysregulation of SNARE-mediated membrane fusion). For additional genes (e.g., CSP, CAPS1/2, and STXBP5/5L [tomosyns]) and paralogs of the eight depicted genes (e.g., VAMP1, SYT2, and UNC13B), such evidence is already accumulating, and the collection of SNAREopathy genes is likely to expand in the future. Mutations in different paralogs may also affect neuronal or synaptic function in different populations of neurons; e.g., UNC13A for excitatory synapses (Augustin et al., 1999). Genes that regulate neuronal SNARE function as part of a generic role in multiple cellular trafficking routes or signal transduction cascades have been excluded; e.g., aSNAP/NSF and kinases and phosphatases. is to define SNAREopathies, chart the landscape of resultant sists of MUNC18-1 bound to syntaxin-1 in a closed configuration neurodevelopmental conditions with its complexity in symptoms in which the SNARE motif formation is buried and unavailable for and disease mechanisms, and suggest explanations for this di- SNARE complex formation (Misura et al., 2000; Rizo and Sudhof,€ versity by considering partial redundancies and a heterogeneous 2012; Toonen and Verhage, 2007). Although, in this configura- effect among different neurons in the brain. Investigating these tion, the SNARE motif is occluded, it forms the starting point suggestions will improve connections between disturbed molec- for SNARE complex assembly (Ma et al., 2013; Schollmeier ular function of the synaptic secretion machinery and the highly et al., 2011). MUNC13-1 disinhibits this autoinhibitory syntaxin: diverse clinical symptomatology and ultimately define outcome MUNC18-1 complex and enables interactions with VAMP2 (Par- measures to evaluate future treatments.