Positive association of the human STON2 gene with schizophrenia

Luan, Zhilin; Zhang, Yanling; Lu, Tianlan; Ruan, Yan; Zhang, Hongyan; Yan, Junhao; Li, Lingzhi; Sun, Wei; Wang, Lifang; Yue, Weihua; Zhang, Dai

doi:10.1097/wnr.0b013e328345ac22

Cited by 15 publications

(18 citation statements)

References 1 publication

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“…Whether the reduced levels of Syt1 observed in SV2A/B/Stn2 TKO neurons are indeed the result of facilitated Syt1 degradation will need to be addressed in future studies. Given the putative genetic association of Stn2 with neuropsychiatric disorders including schizophrenia and autism spectrum disorders (24, 39, 40) and the role of SV2A in late onset Alzheimer’s disease (41) and as a major target of the antiepileptic drug levetiracetam (42, 43), our results may also be of relevance for the diagnosis and treatment of neurological disorders in humans.…”

Section: Discussionmentioning

confidence: 87%

Overlapping functions of stonin 2 and SV2 in sorting of the calcium sensor synaptotagmin 1 to synaptic vesicles

Kaempf

Kochlamazashvili

Puchkov

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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SignificanceBrain function depends on neurotransmission, and alterations in this process are linked to neurological disorders. Neurotransmitter release requires the rapid recycling of synaptic vesicles (SVs) by endocytosis. How synapses maintain the molecular composition of SVs during recycling is poorly understood. We demonstrate that overlapping functions of two completely distinct proteins, the vesicle protein SV2A/B and the adaptor stonin 2, mediate endocytic sorting of the vesicular calcium sensor synaptotagmin 1. As SV2A is the target of the commonly used antiepileptic drug levetiracetam and is linked to late onset Alzheimer’s disease, our findings bear implications for the treatment of neurological and neurodegenerative disorders.

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Section: Discussionmentioning

confidence: 87%

Overlapping functions of stonin 2 and SV2 in sorting of the calcium sensor synaptotagmin 1 to synaptic vesicles

Kaempf

Kochlamazashvili

Puchkov

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…These alterations resemble arousal seeking and impulsivity observed in patients suffering from Tourette syndrome (35) or schizophrenia (36). Recent data from human genetics have indeed revealed a possible association of Stn2 with such neuropsychiatric disorders including schizophrenia and autism-spectrum disorders (37,38). Hence, the work reported here could serve as a starting point for the dissection of the molecular mechanisms underlying these neuropsychiatric disorders.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, loss of Stn2 causes increased locomotion-and exploration-related behaviors in mice. This phenotype resembles arousal seeking and impulsivity observed in patients suffering from Tourette syndrome (35) or schizophrenia (36), which are neuropsychiatric disorders linked to mutations in Stn2 in humans (37,38).…”

Section: Resultsmentioning

confidence: 99%

Compromised fidelity of endocytic synaptic vesicle protein sorting in the absence of stonin 2

Kononenko

Diril

Puchkov

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Neurotransmission depends on the exocytic fusion of synaptic vesicles (SVs) and their subsequent reformation either by clathrinmediated endocytosis or budding from bulk endosomes. How synapses are able to rapidly recycle SVs to maintain SV pool size, yet preserve their compositional identity, is poorly understood. We demonstrate that deletion of the endocytic adaptor stonin 2 (Stn2) in mice compromises the fidelity of SV protein sorting, whereas the apparent speed of SV retrieval is increased. Loss of Stn2 leads to selective missorting of synaptotagmin 1 to the neuronal surface, an elevated SV pool size, and accelerated SV protein endocytosis. The latter phenotype is mimicked by overexpression of endocytosisdefective variants of synaptotagmin 1. Increased speed of SV protein retrieval in the absence of Stn2 correlates with an upregulation of SV reformation from bulk endosomes. Our results are consistent with a model whereby Stn2 is required to preserve SV protein composition but is dispensable for maintaining the speed of SV recycling.pHluorin | hippocampus | mossy fibers N eurotransmission involves the calcium-regulated fusion of synaptic vesicles (SVs), a process that requires the SV calcium sensor synaptotagmin (Syt) (1) and components of the active zone (AZ) that define sites of neurotransmitter release (2). Postexocytic fusion SV membranes are retrieved by endocytosis from the plasma membrane (2-5) to regenerate SVs of the correct size and composition (6). Alternatively, SVs can also be reformed from large plasma membrane infoldings and from endosomes (7) via a brefeldin A-sensitive pathway (8) that may become particularly important under conditions of sustained high-level activity and involves endosomal adaptor complexes such as adaptor protein complex 1 (AP-1) (9, 10). Maintenance of the SV pool requires that the number of recycled SVs closely matches those having undergone exocytosis. As SVs are characterized by a precise protein composition (11) that at least for some SV proteins including Syt1, VGLUT1, and SV2A displays little intervesicle variation (12), molecular mechanisms must exist to control the fidelity of SV protein sorting while maintaining the speed of exo-endocytosis.The mechanisms by which exo-endocytic balance and the fidelity of SV protein sorting are maintained are unknown. One possibility is that retrieval of SV proteins involves clustering (13,14), which would alleviate a need for specific sorting, even if multiple pathways of SV reformation are used (9, 10). However, data based on imaging of SV proteins tagged with the GFPderived pH sensor pHluorin indicate that exocytosed and newly endocytosed SV proteins are not identical, suggesting that intermixing between exocytosed and preexisting surface pools of vesicle proteins occurs (15,16). If SVs lose their identity over multiple rounds of exo-endocytosis, specific mechanisms should exist for the cargo-specific recognition and sorting of SV proteins, e.g., by adaptors (4, 15).Several components of the endocytic machinery may function as a...

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“…Pro307Ser polymorphism is adjacent to an Asn-Pro-Phe or NPF motif, which may mediate the interaction of stonin2 with intersectin and Eps15, as well as the haplotype C-C of Ser307Pro and Ala851Ser polymorphisms (Pro307-Ala851), which affects the stonin2 function that mediates the etiopathogenesis of schizophrenia [33]. In the present study, no significant difference was found in the frequencies of both Ser307Pro and Ala851Ser polymorphisms in STON2 gene, either genotype-wise or allele-wise, between patients with schizophrenia and healthy controls.…”

Section: Discussionmentioning

confidence: 99%

“…Transport, fusion, and recycling of SV affected the normal synaptic function and were critical in maintaining the ability of the synapse to release a neurotransmitter based on sustained stimulation [30], [31], [32]. Two exonic single-nucleotide polymorphisms (SNPs) of the STON2 gene were associated with schizophrenia in a Chinese population [33]. The present study aimed to investigate the relationship between the genetic of the STON2 gene and the cortical surface area in patients with schizophrenia and healthy controls.…”

Section: Introductionmentioning

confidence: 96%

Cortical Surface Area Correlates with STON2 Gene Ser307Pro Polymorphism in First-Episode Treatment-Naïve Patients with Schizophrenia

Xiang

Wang

et al. 2013

PLoS ONE

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BackgroundEvidence shows that STON2 gene is associated with synaptic function and schizophrenia. This study aims to explore the relationship between two functional polymorphisms (Ser307Pro and Ala851Ser) of STON2 gene and the cortical surface area in first-episode treatment-naïve patients with schizophrenia and healthy controls.Methodology/Principal FindingsMagnetic resonance imaging of the whole cortical surface area, which was computed by an automated surface-based technique (FreeSurfer), was obtained from 74 first-episode treatment-naïve patients with schizophrenia and 55 healthy controls. Multiple regression analysis was performed to investigate the effect of genotype subgroups on the cortical surface area. A significant genotype-by-diagnosis effect on the cortical surface area was observed. Pro-allele carriers of Ser307Pro polymorphism had larger right inferior temporal surface area than Ser/Ser carriers in the patients with schizophrenia; however, no significant difference was found in the same area in the healthy controls. The Ala851Ser polymorphism of STON2 gene was not significantly associated with the cortical surface area in patients with schizophrenia and healthy controls.Conclusions/SignificanceThe present study demonstrated that the functional variant of the STON2 gene could alter cortical surface area on the right inferior temporal and contribute to the pathogenesis of schizophrenia.

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Positive association of the human STON2 gene with schizophrenia

Cited by 15 publications

References 1 publication

Overlapping functions of stonin 2 and SV2 in sorting of the calcium sensor synaptotagmin 1 to synaptic vesicles

Overlapping functions of stonin 2 and SV2 in sorting of the calcium sensor synaptotagmin 1 to synaptic vesicles

Compromised fidelity of endocytic synaptic vesicle protein sorting in the absence of stonin 2

Cortical Surface Area Correlates with STON2 Gene Ser307Pro Polymorphism in First-Episode Treatment-Naïve Patients with Schizophrenia

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