2023 Nov 15;24(1):261. doi: 10.1186/s13059-023-03092-8.

Dissecting the autism-associated 16p11.2 locus identifies multiple drivers in neuroanatomical phenotypes and unveils a male-specific role for the major vault protein

Perrine F Kretz ¹, Christel Wagner ¹, Anna Mikhaleva ², Charlotte Montillot ³, Sylvain Hugel ⁴, Ilaria Morella ⁵, Meghna Kannan ¹, Marie-Christine Fischer ¹, Maxence Milhau ³, Ipek Yalcin ⁴, Riccardo Brambilla ^5 6, Mohammed Selloum ^1 7, Yann Herault ^1 7, Alexandre Reymond ², Stephan C Collins ^1 8, Binnaz Yalcin ^9 10

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• PMID: 37968726
• PMCID: PMC10647150
• DOI: 10.1186/s13059-023-03092-8

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Abstract

Background: Using mouse genetic studies and systematic assessments of brain neuroanatomical phenotypes, we set out to identify which of the 30 genes causes brain defects at the autism-associated 16p11.2 locus.

Results: We show that multiple genes mapping to this region interact to regulate brain anatomy, with female mice exhibiting far fewer brain neuroanatomical phenotypes. In male mice, among the 13 genes associated with neuroanatomical defects (Mvp, Ppp4c, Zg16, Taok2, Slx1b, Maz, Fam57b, Bola2, Tbx6, Qprt, Spn, Hirip3, and Doc2a), Mvp is the top driver implicated in phenotypes pertaining to brain, cortex, hippocampus, ventricles, and corpus callosum sizes. The major vault protein (MVP), the main component of the vault organelle, is a conserved protein found in eukaryotic cells, yet its function is not understood. Here, we find MVP expression highly specific to the limbic system and show that Mvp regulates neuronal morphology, postnatally and specifically in males. We also recapitulate a previously reported genetic interaction and show that Mvp^+/-;Mapk3^+/- mice exhibit behavioral deficits, notably decreased anxiety-like traits detected in the elevated plus maze and open field paradigms.

Conclusions: Our study highlights multiple gene drivers in neuroanatomical phenotypes, interacting with each other through complex relationships. It also provides the first evidence for the involvement of the major vault protein in the regulation of brain size and neuroanatomy, specifically in male mice.

Ryanodine receptor type 1 content decrease-induced endoplasmic reticulum stress is a hallmark of myopathies

Jeremy Vidal ¹, Eric A Fernandez ², Martin Wohlwend ³, Pirkka-Pekka Laurila ⁴, Andrea Lopez-Mejia ², Julien Ochala ⁵, Alexander J Lobrinus ^6 7, Bengt Kayser ¹, Isabel C Lopez-Mejia ², Nicolas Place ¹, Nadège Zanou ¹

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• PMID: 37964752
• DOI: 10.1002/jcsm.13349

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Abstract

Background: Decreased ryanodine receptor type 1 (RyR1) protein levels are a well-described feature of recessive RYR1-related myopathies. The aim of the present study was twofold: (1) to determine whether RyR1 content is also decreased in other myopathies and (2) to investigate the mechanisms by which decreased RyR1 protein triggers muscular disorders.

Methods: We used publicly available datasets, muscles from human inflammatory and mitochondrial myopathies, an inducible muscle-specific RYR1 recessive mouse model and RyR1 knockdown in C2C12 muscle cells to measure RyR1 content and endoplasmic reticulum (ER) stress markers. Proteomics, lipidomics, molecular biology and transmission electron microscopy approaches were used to decipher the alterations associated with the reduction of RyR1 protein levels.

Results: RYR1 transcripts were reduced in muscle samples of patients suffering from necrotizing myopathy (P = 0.026), inclusion body myopathy (P = 0.003), polymyositis (P < 0.001) and juvenile dermatomyositis (P < 0.001) and in muscle samples of myotonic dystrophy type 2 (P < 0.001), presymptomatic (P < 0.001) and symptomatic (P < 0.001) Duchenne muscular dystrophy, Becker muscular dystrophy (P = 0.004) and limb-girdle muscular dystrophy type 2A (P = 0.004). RyR1 protein content was also significantly decreased in inflammatory myopathy (-75%, P < 0.001) and mitochondrial myopathy (-71%, P < 0.001) muscles. Proteomics data showed that depletion of RyR1 protein in C2C12 myoblasts leads to myotubes recapitulating the common molecular alterations observed in myopathies. Mechanistically, RyR1 protein depletion reduces ER-mitochondria contact length (-26%, P < 0.001), Ca²⁺ transfer to mitochondria (-48%, P = 0.002) and the mitophagy gene Parkinson protein 2 transcripts (P = 0.037) and induces mitochondrial accumulation (+99%, P = 0.005) and dysfunction (P < 0.001). This was associated to the accumulation of deleterious sphingolipid species. Our data showed increased levels of the ER stress marker chaperone-binding protein/glucose regulated protein 78, GRP78-Bip, in RyR1 knockdown myotubes (+45%, P = 0.046), in mouse RyR1 recessive muscles (+58%, P = 0.001) and in human inflammatory (+96%, P = 0.006) and mitochondrial (+64%, P = 0.049) myopathy muscles. This was accompanied by increased protein levels of the pro-apoptotic protein CCAAT-enhancer-binding protein homologous protein, CHOP-DDIT3, in RyR1 knockdown myotubes (+27%, P < 0.001), mouse RyR1 recessive muscles (+63%, P = 0.009), human inflammatory (+50%, P = 0.038) and mitochondrial (+51%, P = 0.035) myopathy muscles. In publicly available datasets, the decrease in RYR1 content in myopathies was also associated to increased ER stress markers and RYR1 transcript levels are inversely correlated with ER stress markers in the control population.

Conclusions: Decreased RyR1 is commonly observed in myopathies and associated to ER stress in vitro, in mouse muscle and in human myopathy muscles, suggesting a potent role of RyR1 depletion-induced ER stress in the pathogenesis of myopathies.

Global analysis of suppressor mutations that rescue human genetic defects.

Betül Ünlü ^# 1, Carles Pons ^# 2, Uyen Linh Ho ¹, Amandine Batté ¹, Patrick Aloy ^2 3, Jolanda van Leeuwen ⁴

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• PMID: 37821946
• PMCID: PMC10568808
• DOI: 10.1186/s13073-023-01232-0

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Abstract

Background: Genetic suppression occurs when the deleterious effects of a primary “query” mutation, such as a disease-causing mutation, are rescued by a suppressor mutation elsewhere in the genome.

Methods: To capture existing knowledge on suppression relationships between human genes, we examined 2,400 published papers for potential interactions identified through either genetic modification of cultured human cells or through association studies in patients.

Results: The resulting network encompassed 476 unique suppression interactions covering a wide spectrum of diseases and biological functions. The interactions frequently linked genes that operate in the same biological process. Suppressors were strongly enriched for genes with a role in stress response or signaling, suggesting that deleterious mutations can often be buffered by modulating signaling cascades or immune responses. Suppressor mutations tended to be deleterious when they occurred in absence of the query mutation, in apparent contrast with their protective role in the presence of the query. We formulated and quantified mechanisms of genetic suppression that could explain 71% of interactions and provided mechanistic insight into disease pathology. Finally, we used these observations to predict suppressor genes in the human genome.

Conclusions: The global suppression network allowed us to define principles of genetic suppression that were conserved across diseases, model systems, and species. The emerging frequency of suppression interactions among human genes and range of underlying mechanisms, together with the prevalence of suppression in model organisms, suggest that compensatory mutations may exist for most genetic diseases.

Meta-analysis of dispensable essential genes and their interactions with bypass suppressors.

Carles Pons ¹, Jolanda van Leeuwen ²

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• PMID: 37918966
• PMCID: PMC10622647
• DOI: 10.26508/lsa.202302192

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Abstract

Genes have been historically classified as essential or non-essential based on their requirement for viability. However, genomic mutations can sometimes bypass the requirement for an essential gene, challenging the binary classification of gene essentiality. Such dispensable essential genes represent a valuable model for understanding the incomplete penetrance of loss-of-function mutations often observed in natural populations. Here, we compiled data from multiple studies on essential gene dispensability in Saccharomyces cerevisiae to comprehensively characterize these genes. In analyses spanning different evolutionary timescales, dispensable essential genes exhibited distinct phylogenetic properties compared with other essential and non-essential genes. Integration of interactions with suppressor genes that can bypass the gene essentiality revealed the high functional modularity of the bypass suppression network. Furthermore, dispensable essential and bypass suppressor gene pairs reflected simultaneous changes in the mutational landscape of S. cerevisiae strains. Importantly, species in which dispensable essential genes were non-essential tended to carry bypass suppressor mutations in their genomes. Overall, our study offers a comprehensive view of dispensable essential genes and illustrates how their interactions with bypass suppressors reflect evolutionary outcomes.

Exploring the brain epitranscriptome: perspectives from the NSAS summit

Sung-Min Lee ^1 2, Bonsang Koo ^1 2, Clément Carré ³, André Fischer ⁴, Chuan He ^5 6, Ajeet Kumar ^1 2, Kathy Liu ⁷, Kate D Meyer ^8 9, Guo-Li Ming ^{10 11 12 13}, Junmin Peng ^14 15, Jean-Yves Roignant ^16 17, Erik Storkebaum ¹⁸, Shuying Sun ¹⁹, Davide De Pietri Tonelli ²⁰, Yinsheng Wang ²¹, Yi-Lan Weng ²², Luigi Pulvirenti ²³, Yanhong Shi ²⁴, Ki-Jun Yoon ^1 2, Hongjun Song ^{10 11 12 25}

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• PMID: 37928731
• PMCID: PMC10625424
• DOI: 10.3389/fnins.2023.1291446

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Abstract

Increasing evidence reinforces the essential function of RNA modifications in development and diseases, especially in the nervous system. RNA modifications impact various processes in the brain, including neurodevelopment, neurogenesis, neuroplasticity, learning and memory, neural regeneration, neurodegeneration, and brain tumorigenesis, leading to the emergence of a new field termed neuroepitranscriptomics. Deficiency in machineries modulating RNA modifications has been implicated in a range of brain disorders from microcephaly, intellectual disability, seizures, and psychiatric disorders to brain cancers such as glioblastoma. The inaugural NSAS Challenge Workshop on Brain Epitranscriptomics hosted in Crans-Montana, Switzerland in 2023 assembled a group of experts from the field, to discuss the current state of the field and provide novel translational perspectives. A summary of the discussions at the workshop is presented here to simulate broader engagement from the general neuroscience field.

Elafibranor upregulates the EMT-inducer S100A4 via PPARβ/δ

Meijian Zhang ¹, Emma Barroso ¹, Maria Ruart ¹, Lucía Peña ¹, Mona Peyman ¹, David Aguilar-Recarte ¹, Marta Montori-Grau ¹, Patricia Rada ², Clara Cugat ¹, Carla Montironi ³, Mohammad Zarei ⁴, Javier Jurado-Aguilar ¹, Antoni Camins ⁵, Jesús Balsinde ⁶, Ángela M Valverde ², Walter Wahli ⁷, Xavier Palomer ¹, Manuel Vázquez-Carrera ⁸

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• PMID: 37783154
• DOI: 10.1016/j.biopha.2023.115623

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Abstract

Elafibranor is a dual peroxisome proliferator-activated receptor (PPAR)α and β/δ agonist that has reached a phase III clinical trial for the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we examined the effects of elafibranor in mice fed a choline-deficient high-fat diet (CD-HFD), a model of metabolic dysfunction-associated steatohepatitis (MASH) that presents obesity and insulin resistance. Our findings revealed that elafibranor treatment ameliorated steatosis, inflammation, and fibrogenesis in the livers of CD-HFD-fed mice. Unexpectedly, elafibranor also increased the levels of the epithelial-mesenchymal transition (EMT)-promoting protein S100A4 via PPARβ/δ activation. The increase in S100A4 protein levels caused by elafibranor was accompanied by changes in the levels of markers associated with the EMT program. The S100A4 induction caused by elafibranor was confirmed in the BRL-3A rat liver cells and a mouse primary hepatocyte culture. Furthermore, elafibranor reduced the levels of ASB2, a protein that promotes S100A4 degradation, while ASB2 overexpression prevented the stimulating effect of elafibranor on S100A4. Collectively, these findings reveal an unexpected hepatic effect of elafibranor on increasing S100A4 and promoting the EMT program.