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Review | Open Access

Advances in STXBP1 encephalopathy research and translational opportunities

Yi Zhenga,1( )Feiyang Lia,1Jingming Shib( )
Laboratory of Ageing Research, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610054, Sichuan, China
Key Laboratory for Molecular Genetic Mechanisms and Intervention Research on High Altitude Disease of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang 712082, Shaanxi, China

1 These authors contributed equally.

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Graphical Abstract

STXBP1 encephalopathy is caused by disease-causing mutations in the STXBP1 gene.

Abstract

STXBP1 encephalopathy (STXBP1-E) is a rare neurodevelopmental disorder that includes epilepsy; it is caused by de novo STXBP1 mutations. In clinical settings, pharmaceutical interventions to treat STXBP1-E predominantly concentrate on seizure control. However, effective treatments for seizure recurrence, treatment resistance, and common comorbidities remain scarce. Patients with STXBP1-E display a wide range of pathogenic variations that manifest as loss-of-function, gain-of-function, or dominant-negative effects. However, recent studies have primarily investigated the pathogenic mechanisms resulting from loss-of-function mutations using STXBP1 haploinsufficiency models. This approach fails to accurately assess the impact of disease-causing mutations. Moreover, to evaluate new syntaxin-binding protein 1 (STXBP1)-targeting drugs, novel models that incorporate disease-causing mutations or even the genetic backgrounds of patients are needed. Here, we discuss the clinical symptoms of STXBP1-E and the relationship between this disorder and STXBP1 mutations. We also review recent progress toward understanding the biological function of STXBP1 and its deficiency-induced cellular defects. We then discuss recent discoveries concerning the pathogenesis of STXBP1-E and the limitations and challenges associated with the current research model. Additionally, we underscore the value of leveraging stem cell technology to study the pathogenic mechanisms of STXBP1-E, and review stem cell transplantation as a potential approach for treating this disorder. We also discuss potential future research directions that need to be resolved.

References

1

Stamberger H, Nikanorova M, Willemsen MH, et al. STXBP1 encephalopathy: a neurodevelopmental disorder including epilepsy. Neurology. 2016;86(10):954–962. https://doi.org/10.1212/WNL.0000000000002457.

2

López-Rivera JA, Pérez-Palma E, Symonds J, et al. A catalogue of new incidence estimates of monogenic neurodevelopmental disorders caused by de novo variants. Brain. 2020;143(4):1099–1105. https://doi.org/10.1093/brain/awaa051.

3
Mercimek-Andrews S. STXBP1 encephalopathy with epilepsy. In: Adam MP, Feldman J, Mirzaa GM, eds. GeneReviews® [Internet]. Seattle (WA): University of Washington, USA; 2016:1993–2023.
4

Xian JL, Thalwitzer KM, McKee J, et al. Delineating clinical and developmental outcomes in STXBP1-related disorders. Brain. 2023;146(12):5182–5197. https://doi.org/10.1093/brain/awad287.

5

Xian JL, Parthasarathy S, Ruggiero SM, et al. Assessing the landscape of STXBP1-related disorders in 534 individuals. Brain. 2022;145(5):1668–1683. https://doi.org/10.1093/brain/awab327.

6

Kovacevic J, Maroteaux G, Schut D, et al. Protein instability, haploinsufficiency, and cortical hyper-excitability underlie STXBP1 encephalopathy. Brain. 2018;141(5):1350–1374. https://doi.org/10.1093/brain/awy046.

7

Guiberson NGL, Pineda A, Abramov D, et al. Mechanism-based rescue of Munc 18-1 dysfunction in varied encephalopathies by chemical chaperones. Nat Commun. 2018;9(1):3986. https://doi.org/10.1038/s41467-018-06507-4.

8

Lammertse HCA, van Berkel AA, Iacomino M, et al. Homozygous STXBP1 variant causes encephalopathy and gain-of-function in synaptic transmission. Brain. 2020;143(2):441–451. https://doi.org/10.1093/brain/awz391.

9

Houtman SJ, Lammertse HCA, van Berkel AA, et al. STXBP1 syndrome is characterized by inhibition-dominated dynamics of resting-state EEG. Front Physiol. 2021;12:775172. https://doi.org/10.3389/fphys.2021.775172.

10
Yau I, Go C, Jain P, et al. VNS in children with STXBP1-DEE: report of 4 cases; 2023. https://aesnet.org/abstractslisting/vns-in-children-with-stxbp1-dee-report-of-4-cases. Accessed January 12, 2024.
11

Weckhuysen S, Holmgren P, Hendrickx R, et al. Reduction of seizure frequency after epilepsy surgery in a patient with STXBP1 encephalopathy and clinical description of six novel mutation carriers. Epilepsia. 2013;54(5):e74–e80. https://doi.org/10.1111/epi.12124.

12

Brunger AT, Choi UB, Lai Y, et al. The pre-synaptic fusion machinery. Curr Opin Struct Biol. 2019;54:179–188. https://doi.org/10.1016/j.sbi.2019.03.007.

13

Südhof TC. Neurotransmitter release: the last millisecond in the life of a synaptic vesicle. Neuron. 2013;80(3):675–690. https://doi.org/10.1016/j.neuron.2013.10.022.

14

Geppert M, Goda Y, Hammer RE, et al. Synaptotagmin Ⅰ: a major Ca2+ sensor for transmitter release at a central synapse. Cell. 1994;79(4):717–727. https://doi.org/10.1016/0092-8674(94)90556-8.

15

Weber T, Zemelman BV, McNew JA, et al. SNAREpins: minimal machinery for membrane fusion. Cell. 1998;92(6):759–772. https://doi.org/10.1016/s0092-8674(00)81404-x.

16

Chen Y, Wang YH, Zheng Y, et al. Synaptotagmin-1 interacts with PI(4, 5)P2 to initiate synaptic vesicle docking in hippocampal neurons. Cell Rep. 2021;34(11):108842. https://doi.org/10.1016/j.celrep.2021.108842.

17

Südhof TC, Rothman JE. Membrane fusion: grappling with SNARE and SM proteins. Science. 2009;323(5913):474–477. https://doi.org/10.1126/science.1161748.

18

Wang S, Li Y, Gong JH, et al. Munc18 and Munc13 serve as a functional template to orchestrate neuronal SNARE complex assembly. Nat Commun. 2019;10(1):69. https://doi.org/10.1038/s41467-018-08028-6.

19

Jiao JY, He MZ, Port SA, et al. Munc18-1 catalyzes neuronal SNARE assembly by templating SNARE association. Elife. 2018;7:e41771. https://doi.org/10.7554/eLife.41771.

20

Toonen RFG, Wierda K, Sons MS, et al. Munc18-1 expression levels control synapse recovery by regulating readily releasable pool size. Proc Natl Acad Sci USA. 2006;103(48):18332–18337. https://doi.org/10.1073/pnas.0608507103.

21

Abramov D, Guiberson NGL, Burré J. STXBP1 encephalopathies: clinical spectrum, disease mechanisms, and therapeutic strategies. J Neurochem. 2021;157(2):165–178. https://doi.org/10.1111/jnc.15120.

22

Santos TC, Wierda K, Broeke JH, et al. Early Golgi abnormalities and neurodegeneration upon loss of presynaptic proteins Munc18-1, syntaxin-1, or SNAP-25. J Neurosci. 2017;37(17):4525–4539. https://doi.org/10.1523/jneurosci.3352-16.2017.

23

Hamada N, Iwamoto I, Tabata H, et al. MUNC18-1 gene abnormalities are involved in neurodevelopmental disorders through defective cortical architecture during brain development. Acta Neuropathol Commun. 2017;5(1):92. https://doi.org/10.1186/s40478-017-0498-5.

24

van Berkel AA, Santos TC, Shaweis H, et al. Loss of MUNC18-1 leads to retrograde transport defects in neurons. J Neurochem. 2021;157(3):450–466. https://doi.org/10.1111/jnc.15256.

25

Feringa FM, van Berkel AA, Nair A, et al. An atypical, staged cell death pathway induced by depletion of SNARE-proteins MUNC18-1 or syntaxin-1. J Neurosci. 2023;43(3):347–358. https://doi.org/10.1523/jneurosci.0611-22.2022.

26

Law C, Schaan Profes M, Levesque M, et al. Normal molecular specification and neurodegenerative disease-like death of spinal neurons lacking the SNARE-associated synaptic protein Munc18-1. J Neurosci. 2016;36(2):561–576. https://doi.org/10.1523/JNEUROSCI.1964-15.2016.

27

van Berkel AA, Koopmans F, Gonzalez-Lozano MA, et al. Dysregulation of synaptic and developmental transcriptomic/proteomic profiles upon depletion of MUNC18-1. eNeuro. 2022;9(6). https://doi.org/10.1523/ENEURO.0186-22.2022.ENEURO.0186eENEURO.0122.2022.

28

Chai YJ, Sierecki E, Tomatis VM, et al. Munc18-1 is a molecular chaperone for α-synuclein, controlling its self-replicating aggregation. J Cell Biol. 2016;214(6):705–718. https://doi.org/10.1083/jcb.201512016.

29

de Wit H, Walter AM, Milosevic I, et al. Synaptotagmin-1 docks secretory vesicles to syntaxin-1/SNAP-25 acceptor complexes. Cell. 2009;138(5):935–946. https://doi.org/10.1016/j.cell.2009.07.027.

30

Pons-Vizcarra M, Kurps J, Tawfik B, et al. Correction: MUNC18-1 regulates the submembrane F-actin network, independently of syntaxin1 targeting, via hydrophobicity in β-sheet 10. J Cell Sci. 2019;132(24):jcs242552. https://doi.org/10.1242/jcs.242552.

31
André T, van Berkel AA, Singh G, et al. Reduced protein stability of 11 pathogenic missense STXBP1/MUNC18-1 variants and improved disease prediction. Biol Psychiatr. 2024;S0006–S3223(24). https://doi.org/10.1016/j.bio-psych.2024.03.007, 01145–4.
32

Guiberson NGL, Black LS, Haller JE, et al. Disease-linked mutations in Munc18-1 deplete synaptic Doc2. Brain. 2024:awae019. https://doi.org/10.1093/brain/awae019.

33

Lanoue V, Chai YJ, Brouillet JZ, et al. STXBP1 encephalopathy: connecting neurodevelopmental disorders with α-synucleinopathies? Neurology. 2019;93(3):114–123. https://doi.org/10.1212/WNL.0000000000007786.

34

Abramov D, Guiberson NGL, Daab A, et al. Targeted stabilization of Munc18-1 function via pharmacological chaperones. EMBO Mol Med. 2021;13(1):e12354. https://doi.org/10.15252/emmm.202012354.

35

Novick P, Schekman R. Secretion and cell-surface growth are blocked in a temperature-sensitive mutant of Saccharomyces cerevisiae. Proc Natl Acad Sci U S A. 1979;76(4):1858–1862. https://doi.org/10.1073/pnas.76.4.1858.

36

Peng Y, Lee JE, Rowland K, et al. Regulation of dendrite growth and maintenance by exocytosis. J Cell Sci. 2015;128(23):4279–4292. https://doi.org/10.1242/jcs.174771.

37

Zhu BF, Mak JCH, Morris AP, et al. Functional analysis of epilepsy-associated variants in STXBP1/Munc18-1 using humanized Caenorhabditis elegans. Epilepsia. 2020;61(4):810–821. https://doi.org/10.1111/epi.16464.

38

Grone BP, Marchese M, Hamling KR, et al. Epilepsy, behavioral abnormalities, and physiological comorbidities in syntaxin-binding protein 1 (STXBP1) mutant zebrafish. PLoS One. 2016;11(3):e0151148. https://doi.org/10.1371/journal.pone.0151148.

39

Verhage M, Maia AS, Plomp JJ, et al. Synaptic assembly of the brain in the absence of neurotransmitter secretion. Science. 2000;287(5454):864–869. https://doi.org/10.1126/science.287.5454.864.

40

Hager T, Maroteaux G, du Pont P, et al. Munc18-1 haploinsufficiency results in enhanced anxiety-like behavior as determined by heart rate responses in mice. Behav Brain Res. 2014;260:44–52. https://doi.org/10.1016/j.bbr.2013.11.033.

41

Miyamoto H, Tatsukawa T, Shimohata A, et al. Impaired cortico-striatal excitatory transmission triggers epilepsy. Nat Commun. 2019;10(1):1917. https://doi.org/10.1038/s41467-019-09954-9.

42

Miyamoto H, Shimohata A, Abe M, et al. Potentiation of excitatory synaptic transmission ameliorates aggression in mice with Stxbp1 haploinsufficiency. Hum Mol Genet. 2017;26(24):4961–4974. https://doi.org/10.1093/hmg/ddx379.

43

Chen W, Cai ZL, Chao ES, et al. Stxbp1/Munc18-1 haploinsufficiency impairs inhibition and mediates key neurological features of STXBP1 encephalopathy. Elife. 2020;9:e48705. https://doi.org/10.7554/eLife.48705.

44

Kim JH, Chen W, Chao ES, et al. GABAergic/glycinergic and glutamatergic neurons mediate distinct neurodevelopmental phenotypes of STXBP1 encephalopathy. J Neurosci. 2024;44(14):e1806232024. https://doi.org/10.1523/jneurosci.1806-23.2024.

45

Lu Z, He S, Jiang J, et al. Base-edited Cynomolgus Monkeys mimic core symptoms of STXBP1 encephalopathy. Mol Ther. 2022;30(6):2163–2175. https://doi.org/10.1016/j.ymthe.2022.03.001.

46

dos Santos AB, Larsen SD, Guo LC, et al. Microcircuit failure in STXBP1 encephalopathy leads to hyperexcitability. Cell Rep Med. 2023;4(12):101308. https://doi.org/10.1016/j.xcrm.2023.101308.

47

Takahashi K, Yamanaka S. A decade of transcription factor-mediated reprogramming to pluripotency. Nat Rev Mol Cell Biol. 2016;17(3):183–193. https://doi.org/10.1038/nrm.2016.8.

48

Yang N, Chanda S, Marro S, et al. Generation of pure GABAergic neurons by transcription factor programming. Nat Methods. 2017;14(6):621–628. https://doi.org/10.1038/nmeth.4291.

49

Zhang YS, Pak C, Han Y, et al. Rapid single-step induction of functional neurons from human pluripotent stem cells. Neuron. 2013;78(5):785–798. https://doi.org/10.1016/j.neuron.2013.05.029.

50

Herdy J, Schafer S, Kim Y, et al. Chemical modulation of transcriptionally enriched signaling pathways to optimize the conversion of fibroblasts into neurons. Elife. 2019;8:41356. https://doi.org/10.7554/elife.41356.

51
Smith C, Ye ZH, Cheng LZ. Genome editing in human pluripotent stem cells. Cold Spring Harb Protoc. 2016;2016(4). https://doi.org/10.1101/pdb.top086819. pdb.top086819.
52

Parent JM, Anderson SA. Reprogramming patient-derived cells to study the epilepsies. Nat Neurosci. 2015;18(3):360–366. https://doi.org/10.1038/nn.3944.

53

Patzke C, Han Y, Covy J, et al. Analysis of conditional heterozygous STXBP1 mutations in human neurons. J Clin Invest. 2015;125(9):3560–3571. https://doi.org/10.1172/JCI78612.

54

Shen C, Liu YH, Yu HJ, et al. The N-peptide–binding mode is critical to Munc18-1 function in synaptic exocytosis. J Biol Chem. 2018;293(47):18309–18317. https://doi.org/10.1074/jbc.ra118.005254.

55

Yamamoto T, Otsu M, Okumura T, et al. Generation of three induced pluripotent stem cell lines from postmortem tissue derived following sudden death of a young patient with STXBP1 mutation. Stem Cell Res. 2019;39:101485. https://doi.org/10.1016/j.scr.2019.101485.

56

Ichise E, Chiyonobu T, Ishikawa M, et al. Impaired neuronal activity and differential gene expression in STXBP1 encephalopathy patient iPSC-derived GABAergic neurons. Hum Mol Genet. 2021;30(14):1337–1348. https://doi.org/10.1093/hmg/ddab113.

57

van Berkel AA, Lammertse HCA, Öttl M, et al. Reduced MUNC18-1 levels, synaptic proteome changes, and altered network activity in STXBP1-related disorder patient neurons. Biol Psychiatry Glob Open Sci. 2024;4(1):284–298. https://doi.org/10.1016/j.bpsgos.2023.05.004.

58

Öttl M, Toonen RF, Verhage M. Reduced synaptic depression in human neurons carrying homozygous disease-causing STXBP1 variant L446F. Hum Mol Genet. 2024:ddae035. https://doi.org/10.1093/hmg/ddae035.

59

McLeod F, Dimtsi A, Marshall AC, et al. Altered synaptic connectivity in an in vitro human model of STXBP1 encephalopathy. Brain. 2023;146(3):850–857. https://doi.org/10.1093/brain/awac396.

60

Colasante G, Rubio A, Massimino L, et al. Direct neuronal reprogramming reveals unknown functions for known transcription factors. Front Neurosci. 2019;13:283. https://doi.org/10.3389/fnins.2019.00283.

61

Paşca SP. Assembling human brain organoids. Science. 2019;363(6423):126–127. https://doi.org/10.1126/science.aau5729.

62

Upadhya D, Attaluri S, Liu Y, et al. Grafted hPSC-derived GABA-ergic interneurons regulate seizures and specific cognitive function in temporal lobe epilepsy. NPJ Regen Med. 2022;7(1):38. https://doi.org/10.1038/s41536-022-00234-7.

63

Zhu Q, Mishra A, Park JS, et al. Human cortical interneurons optimized for grafting specifically integrate, abort seizures, and display prolonged efficacy without over-inhibition. Neuron. 2023;111(6):807–823.e7. https://doi.org/10.1016/j.neuron.2022.12.014.

64

Huang HY, Bach JR, Sharma HS, et al. The 2022 yearbook of neurorestoratology. J Neurorestoratol. 2023;11(2):100054. https://doi.org/10.1016/j.jnrt.2023.100054.

Journal of Neurorestoratology
Article number: 100134
Cite this article:
Zheng Y, Li F, Shi J. Advances in STXBP1 encephalopathy research and translational opportunities. Journal of Neurorestoratology, 2024, 12(3): 100134. https://doi.org/10.1016/j.jnrt.2024.100134

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Received: 11 March 2024
Revised: 22 April 2024
Accepted: 08 May 2024
Published: 10 June 2024
© 2024 The Author(s).

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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