Analyses of the autism-associated neuroligin-3 R451C mutation in human neurons reveal a gain-of-function synaptic mechanism

Wang, Le; Mirabella, Vincent R.; Dai, Rujia; Su, Xiao; Xu, Renfeng; Jadali, Azadeh; Bernabucci, Matteo; Singh, Ishnoor; Chen, Yu; Tian, Jianghua; Jiang, Peng; Kwan, Kelvin Y.; Pak, ChangHui; Liu, Chun Yu; Comoletti, Davide; Hart, Ronald P.; Chen, Chao; Südhof, Thomas C.; Pang, Zhiping P.

doi:10.1038/s41380-022-01834-x

Cited by 14 publications

(9 citation statements)

References 110 publications

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“…Based on our strategy of manipulating splicing as a therapeutic strategy for specific NRXN1 mutations, a similar approach could be applied to loss- and gain-of-function mechanisms linked to mutations in other neuropsychiatric disorder-related synaptic genes (e.g., NLGN3 ( 47 ), CACNA1D ( 48 ), CACNA1C ( 49 ) , SCN2A ( 50 )). Taken together, our work highlights important implications for precision medicine treatments of neuropsychiatric disorders, demonstrating the necessity of functionally dissecting the phenotypic impact of diverse patient-specific genetic variants across cellular contexts, to resolve candidate therapies across stratified disease mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Precise Therapeutic Targeting of DistinctNRXN1^+/-Mutations

Fernando,

Fan,

Zhang

et al. 2023

Preprint

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As genetic studies continue to identify risk loci that are significantly associated with risk for neuropsychiatric disease, a critical unanswered question is the extent to which diverse mutations--sometimes impacting the same gene--will require common or individually tailored therapeutic strategies. Here we consider this in the context of rare, heterozygous, and non-recurrent copy number variants (2p16.3) linked to a variety of neuropsychiatric disorders that impactNRXN1, a pre-synaptic cell adhesion protein that serves as a critical synaptic organizer in the brain. Complex patterns ofNRXN1alternative splicing are fundamental to establishing diverse neurocircuitry, vary between the cell types of the brain, and are differentially impacted by unique patient-specific (non-recurrent) deletions. Progress towards precision medicine may require restoring each person’sNRXN1isoform repertoires in a cell-type-specific manner. Towards this, here we contrast the cell-type-specific impact of unique patient-specific mutations inNRXN1using human induced pluripotent stem cells. Perturbations inNRXN1splicing causally lead to divergent cell-type-specific synaptic outcomes: whereasNRXN1+/−deletions result in a decrease in synaptic activity throughout glutamatergic neuron maturation, there is an unexpected increase in synaptic activity in immature GABAergic neurons. Both glutamatergic and GABAergic synaptic deficits reflect independent loss-of-function (LOF) and gain-of-function (GOF) splicing defects. Towards clinical relevance, we show that treatment with β-estradiol increasesNRXN1expression in glutamatergic neurons, while antisense oligonucleotides knockdown mutant isoform expression across both glutamatergic and GABAergic neurons. Direct or indirect manipulation ofNRXN1splicing isoforms provides a promising therapeutic strategy for treating humans with 2p16.3 deletions.

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Section: Discussionmentioning

confidence: 99%

Precise Therapeutic Targeting of DistinctNRXN1^+/-Mutations

Fernando,

Fan,

Zhang

et al. 2023

Preprint

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“…Several disease-related mutations have been reported for neuroligins, including R55G, V72X, K82Q, N236S, R451C, R471C, P534S, R617W, T659N, L721F, and T812S in NLGN3 ( Supplementary Figure 6A , retrieved from UniProt ID Q9NZ94). Among them, R451C is a well-known mutation that is closely related to the development of ASD ( 70 ) and has recently been found to enhance the gain of function in excitatory synaptic transmission ( 71 ). This residue locates in the central helix of NLGN3 ( Supplementary Figures 6A, B ), and the mutation may affect the intracellular traffic and membrane localization of NLGN3.…”

Section: Discussionmentioning

confidence: 99%

Expression and structural analysis of human neuroligin 2 and neuroligin 3 implicated in autism spectrum disorders

Zhang

Hou²,

Ou³

et al. 2022

Front. Endocrinol.

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The development of autism spectrum disorders (ASDs) involves both environmental factors such as maternal diabetes and genetic factors such as neuroligins (NLGNs). NLGN2 and NLGN3 are two members of NLGNs with distinct distributions and functions in synapse development and plasticity. The relationship between maternal diabetes and NLGNs, and the distinct working mechanisms of different NLGNs currently remain unclear. Here, we first analyzed the expression levels of NLGN2 and NLGN3 in a streptozotocin-induced ASD mouse model and different brain regions to reveal their differences and similarities. Then, cryogenic electron microscopy (cryo-EM) structures of human NLGN2 and NLGN3 were determined. The overall structures are similar to their homologs in previous reports. However, structural comparisons revealed the relative rotations of two protomers in the homodimers of NLGN2 and NLGN3. Taken together with the previously reported NLGN2–MDGA1 complex, we speculate that the distinct assembly adopted by NLGN2 and NLGN3 may affect their interactions with MDGAs. Our results provide structural insights into the potential distinct mechanisms of NLGN2 and NLGN3 implicated in the development of ASD.

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“…The lentivirus generation protocol was previously outlined by Wang et al ( 84 ). Selection with puromycin (1 mg/mL; Sigma Aldrich, catalog# P8833) was carried out for the next 2 days.…”

Section: Methodsmentioning

confidence: 99%

“…Functional analyses of iN cells were conducted using whole-cell patch-clamp electrophysiology as described elsewhere ( 84, 94 ). Miniature postsynaptic currents were recorded at a holding potential of −70 mV in the presence of 1 μM tetrodotoxin (TTX).…”

Section: Methodsmentioning

confidence: 99%

Polygenic Risk for Alcohol Use Disorder Affects Cellular Responses to Ethanol Exposure in a Human Microglial Cell Model

Li,

Liu,

Boreland

et al. 2024

Preprint

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Polygenic risk scores (PRS) assess genetic susceptibility to Alcohol Use Disorder (AUD), yet their molecular implications remain underexplored. Neuroimmune interactions, particularly in microglia, are recognized as significant contributors to AUD pathophysiology. We investigated the interplay between AUD PRS and ethanol in human microglia derived from iPSCs from individuals with high- or low-PRS (HPRS or LPRS) of AUD. Ethanol exposure induced elevated CD68 expression and morphological changes in microglia, with differential responses between HPRS and LPRS microglial cells. Transcriptomic analysis revealed expression differences in MHCII complex and phagocytosis-related genes following ethanol exposure; HPRS microglial cells displayed enhanced phagocytosis and increasedCLEC7Aexpression, unlike LPRS microglial cells. Synapse numbers in co-cultures of induced neurons with microglia after alcohol exposure were lower in HRPS co-cultures, suggesting possible excess synapse pruning. This study provides insights into the intricate relationship between AUD PRS, ethanol, and microglial function, potentially influencing neuronal functions in developing AUD.

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Analyses of the autism-associated neuroligin-3 R451C mutation in human neurons reveal a gain-of-function synaptic mechanism

Cited by 14 publications

References 110 publications

Precise Therapeutic Targeting of DistinctNRXN1^+/-Mutations

Precise Therapeutic Targeting of DistinctNRXN1^+/-Mutations

Expression and structural analysis of human neuroligin 2 and neuroligin 3 implicated in autism spectrum disorders

Polygenic Risk for Alcohol Use Disorder Affects Cellular Responses to Ethanol Exposure in a Human Microglial Cell Model

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Analyses of the autism-associated neuroligin-3 R451C mutation in human neurons reveal a gain-of-function synaptic mechanism

Cited by 14 publications

References 110 publications

Precise Therapeutic Targeting of DistinctNRXN1+/-Mutations

Precise Therapeutic Targeting of DistinctNRXN1+/-Mutations

Expression and structural analysis of human neuroligin 2 and neuroligin 3 implicated in autism spectrum disorders

Polygenic Risk for Alcohol Use Disorder Affects Cellular Responses to Ethanol Exposure in a Human Microglial Cell Model

Contact Info

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Precise Therapeutic Targeting of DistinctNRXN1^+/-Mutations

Precise Therapeutic Targeting of DistinctNRXN1^+/-Mutations