A synthetic synaptic organizer protein restores glutamatergic neuronal circuits

Suzuki, Kenichi; Elegheert, J.; Song, Inseon; Sasakura, Hiroyuki; Senkov, Oleg; Matsuda, Keiko; Kakegawa, Wataru; Clayton, Amber J.; Chang, Veronica T.; Ferrer-Ferrer, Maura; Miura, Eriko; Kaushik, Rahul; Ikeno, Mitsuru; Morioka, Yuki; Takeuchi, Yuka; Shimada, Tatsuya; Otsuka, Shintaro; Stoyanov, Stoyan; Watanabe, Masahiko; Takeuchi, Kosei; Dityatev, Alexander; Aricescu, A. Radu; Yuzaki, Michisuke

doi:10.1126/science.abb4853

Cited by 99 publications

(78 citation statements)

References 92 publications

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“…Neuronal cell death is one of the most critical pathological issues caused by direct mechanical impact, followed by a series of secondary molecular cascades, including mitochondrial damage, reactive oxygen species (ROS) and misfolded protein accumulation, and the inflammatory response [ [2] , [3] , [4] ]. Although neural tissue is associated with limited intrinsic regenerative capability, increasing evidence indicates that targeting these secondary molecular processes is a therapeutic method for improving functional recovery after SCI in many animal cases [ [5] , [6] , [7] ].…”

Section: Introductionmentioning

confidence: 99%

Delivery of pOXR1 through an injectable liposomal nanoparticle enhances spinal cord injury regeneration by alleviating oxidative stress

Zhang

Xiong

et al. 2021

Bioactive Materials

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Oxidation resistance 1 (OXR1) is regarded as a critical regulator of cellular homeostasis in response to oxidative stress. However, the role of OXR1 in the neuronal response to spinal cord injury (SCI) remains undefined. On the other hand, gene therapy for SCI has shown limited success to date due in part to the poor utility of conventional gene vectors. In this study, we evaluated the function of OXR1 in SCI and developed an available carrier for delivering the OXR1 plasmid (pOXR1). We found that OXR1 expression is remarkably increased after SCI and that this regulation is protective after SCI. Meanwhile, we assembled cationic nanoparticles with vitamin E succinate-grafted ε-polylysine (VES-g-PLL) (Nps). The pOXR1 was precompressed with Nps and then encapsulated into cationic liposomes. The particle size of pOXR1 was compressed to 58 nm, which suggests that pOXR1 can be encapsulated inside liposomes with high encapsulation efficiency and stability to enhance the transfection efficiency. The agarose gel results indicated that Nps-pOXR1-Lip eliminated the degradation of DNA by DNase I and maintained its activity, and the cytotoxicity results indicated that pOXR1 was successfully transported into cells and exhibited lower cytotoxicity. Finally, Nps-pOXR1-Lip promoted functional recovery by alleviating neuronal apoptosis, attenuating oxidative stress and inhibiting inflammation. Therefore, our study provides considerable evidence that OXR1 is a beneficial factor in resistance to SCI and that Nps-Lip-pOXR1 exerts therapeutic effects in acute traumatic SCI.

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Section: Introductionmentioning

confidence: 99%

Delivery of pOXR1 through an injectable liposomal nanoparticle enhances spinal cord injury regeneration by alleviating oxidative stress

Zhang

Xiong

et al. 2021

Bioactive Materials

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“…We note that second-generation antipsychotic drugs such as olanzapine and clozapine can enhance neurite outgrowth and increase spine numbers (Critchlow et al, 2006;Lu and Dwyer, 2005). In addition, another study demonstrated an exciting strategy of designing a synthetic synaptic organizer protein to restore dendritic spine numbers, which nally led to the improvement of hippocampus-dependent learning in AD (Suzuki et al, 2020). Moreover, they anticipated that other extracellular scaffold proteins could be used to restore synaptic connectivity in other neurodevelopment and neurodegenerative diseases.…”

Section: Discussionmentioning

confidence: 95%

Analyses of GWAS and sub-threshold loci lead to the discovery of dendrite development and morphology dysfunction underlying schizophrenia genetic risk

Chen¹,

Wang²,

Xu³

et al. 2021

Preprint

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Schizophrenia (SCZ) is highly polygenic, and thousands of genes contribute to its risk. The 145 GWAS loci identified to date do not fully reveal SCZ genetic risk pathways. In this study, we explore a cost-effective strategy to increase power of inference of novel pathways, by expanding the analysis to include sub-threshold GWAS (subGWAS) loci. We identify 180 subGWAS loci (e.g., 5 x10-8 < P ≤ 10-6) based on SCZ summary statistics of 40,675 cases and 64,643 controls from CLOZUK and PGC datasets, and show that subGWAS loci contain substantial true genetic association signals. We merge GWAS (sigGWAS) and subGWAS loci and identify in total 304 high-confidence risk genes (HRGs) by jointly modeling the expanded set of loci. We identify dendrite development and morphogenesis (DDM, GO:0016358 and GO:0048813) as a novel category of biological processes implicated in SCZ genetic risk. SigGWAS loci fail to detect DDM, which is predominantly enriched in subGWAS loci. Further, DDM genes are significantly enriched for heritability of SCZ, as well as bipolar disorder and major depression. Genes in this functional process show cell type specificity in neurons in both fetal and adult brains, and their involvement in SCZ risk is further supported by eQTL analysis of SCZ risk alleles. We derived induced pluripotent stem cell (iPSC) lines from sporadic SCZ patients and normal controls and observe increased neurite lengths and soma sizes in patient-derived iPSC lines along multiple time points during neuronal development, further validating the genetic findings. We also find that the implicated genes are enriched in FDA-approved drug targets, suggesting a therapeutic potential for targeting the implicated biological processes for prevention and treatment. Our results showcase that expanding the analysis to include subGWAS loci is a valuable strategy for enhancing power of uncovering disease mechanisms, especially those of weak effect size, for SCZ and other complex diseases.

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“…Future studies will have to address the expression of the GluA4-ATD isoform and possible physiological functions. In this context, it may be interesting to note, that the GluA4 ATD is involved in pentraxin interactions [96,97]. Less frequent GRIA4 splicing events include the usage of an alternative 5′-UTR exon (GRIA4 (h)), and inclusion of a 39 nt cassette exon before the flop exon (GRIA4 (e, f)), see flip/flop splicing; Fig.…”

Section: Alternative Splicing Of Ampa Receptor Subunitsmentioning

confidence: 99%

Splicing and editing of ionotropic glutamate receptors: a comprehensive analysis based on human RNA-Seq data

Herbrechter

Hube

Buchholz

et al. 2021

Cell. Mol. Life Sci.

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Ionotropic glutamate receptors (iGluRs) play key roles for signaling in the central nervous system. Alternative splicing and RNA editing are well-known mechanisms to increase iGluR diversity and to provide context-dependent regulation. Earlier work on isoform identification has focused on the analysis of cloned transcripts, mostly from rodents. We here set out to obtain a systematic overview of iGluR splicing and editing in human brain based on RNA-Seq data. Using data from two large-scale transcriptome studies, we established a workflow for the de novo identification and quantification of alternative splice and editing events. We detected all canonical iGluR splice junctions, assessed the abundance of alternative events described in the literature, and identified new splice events in AMPA, kainate, delta, and NMDA receptor subunits. Notable events include an abundant transcript encoding the GluA4 amino-terminal domain, GluA4-ATD, a novel C-terminal GluD1 (delta receptor 1) isoform, GluD1-b, and potentially new GluK4 and GluN2C isoforms. C-terminal GluN1 splicing may be controlled by inclusion of a cassette exon, which shows preference for one of the two acceptor sites in the last exon. Moreover, we identified alternative untranslated regions (UTRs) and species-specific differences in splicing. In contrast, editing in exonic iGluR regions appears to be mostly limited to ten previously described sites, two of which result in silent amino acid changes. Coupling of proximal editing/editing and editing/splice events occurs to variable degree. Overall, this analysis provides the first inventory of alternative splicing and editing in human brain iGluRs and provides the impetus for further transcriptome-based and functional investigations.

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A synthetic synaptic organizer protein restores glutamatergic neuronal circuits

Cited by 99 publications

References 92 publications

Delivery of pOXR1 through an injectable liposomal nanoparticle enhances spinal cord injury regeneration by alleviating oxidative stress

Delivery of pOXR1 through an injectable liposomal nanoparticle enhances spinal cord injury regeneration by alleviating oxidative stress

Analyses of GWAS and sub-threshold loci lead to the discovery of dendrite development and morphology dysfunction underlying schizophrenia genetic risk

Splicing and editing of ionotropic glutamate receptors: a comprehensive analysis based on human RNA-Seq data

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