RÉSUMÉ
Lowe Syndrome (LS) is a rare X-linked disorder characterized by renal dysfunction, cataracts, and several central nervous system (CNS) anomalies. The mechanisms underlying the neurological dysfunction in LS remain unclear, albeit they share some phenotypic characteristics similar to the deficiency or dysfunction of the Reelin signaling, a relevant pathway with roles in CNS development and neuronal functions. In this study, we investigated the role of OCRL1, an inositol polyphosphate 5-phosphatase encoded by the OCRL gene, mutated in LS, focusing on its impact on endosomal trafficking and receptor recycling in human neuronal cells. Specifically, we tested the effects of OCRL1 deficiency in the trafficking and signaling of ApoER2/LRP8, a receptor for the ligand Reelin. We found that loss of OCRL1 impairs ApoER2 intracellular trafficking, leading to reduced receptor expression and decreased levels at the plasma membrane. Additionally, human neurons deficient in OCRL1 showed impairments in ApoER2/Reelin-induced responses. Our findings highlight the critical role of OCRL1 in regulating ApoER2 endosomal recycling and its impact on the ApoER2/Reelin signaling pathway, providing insights into potential mechanisms underlying the neurological manifestations of LS.
Sujet(s)
Molécules d'adhérence cellulaire neuronale , Endosomes , Protéines de la matrice extracellulaire , Protéines apparentées au récepteur LDL , Protéines de tissu nerveux , Neurones , Phosphoric monoester hydrolases , Transport des protéines , Protéine reeline , Serine endopeptidases , Humains , Phosphoric monoester hydrolases/métabolisme , Phosphoric monoester hydrolases/génétique , Phosphoric monoester hydrolases/déficit , Protéines de tissu nerveux/métabolisme , Protéines de tissu nerveux/génétique , Protéines de tissu nerveux/déficit , Serine endopeptidases/métabolisme , Serine endopeptidases/génétique , Serine endopeptidases/déficit , Molécules d'adhérence cellulaire neuronale/métabolisme , Molécules d'adhérence cellulaire neuronale/génétique , Molécules d'adhérence cellulaire neuronale/déficit , Protéines de la matrice extracellulaire/métabolisme , Protéines de la matrice extracellulaire/génétique , Protéines de la matrice extracellulaire/déficit , Endosomes/métabolisme , Neurones/métabolisme , Protéines apparentées au récepteur LDL/métabolisme , Protéines apparentées au récepteur LDL/génétique , Transduction du signal , Syndrome de Lowe/génétique , Syndrome de Lowe/métabolismeRÉSUMÉ
Disrupted alternative splicing plays a determinative role in neurological diseases, either as a direct cause or as a driver in disease susceptibility. Transcriptomic profiling of aged human postmortem brain samples has uncovered hundreds of aberrant mRNA splicing events in Alzheimer's disease (AD) brains, associating dysregulated RNA splicing with disease. We previously identified a complex array of alternative splicing combinations across apolipoprotein E receptor 2 (APOER2), a transmembrane receptor that interacts with both the neuroprotective ligand Reelin and the AD-associated risk factor, APOE. Many of the human APOER2 isoforms, predominantly featuring cassette splicing events within functionally important domains, are critical for the receptor's function and ligand interaction. However, a comprehensive repertoire and the functional implications of APOER2 isoforms under both physiological and AD conditions are not fully understood. Here, we present an in-depth analysis of the splicing landscape of human APOER2 isoforms in normal and AD states. Using single-molecule, long-read sequencing, we profiled the entire APOER2 transcript from the parietal cortex and hippocampus of Braak stage IV AD brain tissues along with age-matched controls and investigated several functional properties of APOER2 isoforms. Our findings reveal diverse patterns of cassette exon skipping for APOER2 isoforms, with some showing region-specific expression and others unique to AD-affected brains. Notably, exon 15 of APOER2, which encodes the glycosylation domain, showed less inclusion in AD compared to control in the parietal cortex of females with an APOE É3/É3 genotype. Also, some of these APOER2 isoforms demonstrated changes in cell surface expression, APOE-mediated receptor processing, and synaptic number. These variations are likely critical in inducing synaptic alterations and may contribute to the neuronal dysfunction underlying AD pathogenesis.
Sujet(s)
Épissage alternatif , Maladie d'Alzheimer , Protéines apparentées au récepteur LDL , Protéine reeline , Humains , Maladie d'Alzheimer/génétique , Maladie d'Alzheimer/anatomopathologie , Maladie d'Alzheimer/métabolisme , Protéines apparentées au récepteur LDL/génétique , Protéines apparentées au récepteur LDL/métabolisme , Épissage alternatif/génétique , Isoformes de protéines/génétique , Analyse de séquence d'ARN , Femelle , Sujet âgé , Encéphale/métabolisme , Encéphale/anatomopathologie , Apolipoprotéines E/génétique , Mâle , Hippocampe/métabolisme , Hippocampe/anatomopathologie , Sujet âgé de 80 ans ou plus , Épissage des ARN/génétique , Protéines de tissu nerveux/génétique , Protéines de tissu nerveux/métabolismeRÉSUMÉ
Signals emanating from the T-cell receptor (TCR), co-stimulatory receptors, and cytokine receptors each influence CD8 T-cell fate. Understanding how these signals respond to homeostatic and microenvironmental cues can reveal new ways to therapeutically direct T-cell function. Through forward genetic screening in mice, we discover that loss-of-function mutations in LDL receptor-related protein 10 (Lrp10) cause naive and central memory CD8 T cells to accumulate in peripheral lymphoid organs. Lrp10 encodes a conserved cell surface protein of unknown immunological function. T-cell activation induces Lrp10 expression, which post-translationally suppresses IL7 receptor (IL7R) levels. Accordingly, Lrp10 deletion enhances T-cell homeostatic expansion through IL7R signaling. Lrp10-deficient mice are also intrinsically resistant to syngeneic tumors. This phenotype depends on dense tumor infiltration of CD8 T cells, which display increased memory cell characteristics, reduced terminal exhaustion, and augmented responses to immune checkpoint inhibition. Here, we present Lrp10 as a new negative regulator of CD8 T-cell homeostasis and a host factor that controls tumor resistance with implications for immunotherapy.
Sujet(s)
Lymphocytes T CD8+ , Homéostasie , Récepteurs à l'interleukine-7 , Animaux , Lymphocytes T CD8+/immunologie , Lymphocytes T CD8+/métabolisme , Souris , Récepteurs à l'interleukine-7/métabolisme , Récepteurs à l'interleukine-7/génétique , Protéines apparentées au récepteur LDL/métabolisme , Protéines apparentées au récepteur LDL/génétique , Transduction du signal , Activation des lymphocytes/immunologie , Souris knockout , Souris de lignée C57BL , Mémoire immunologique , Tumeurs/immunologie , Tumeurs/génétique , HumainsRÉSUMÉ
Lung cancer is the leading cause of cancer-related deaths in the world, and non-small cell lung cancer (NSCLC) is the most common subset. We previously found that infiltration of tumor inflammatory monocytes (TIMs) into lung squamous carcinoma (LUSC) tumors is associated with increased metastases and poor survival. To further understand how TIMs promote metastases, we compared RNA-Seq profiles of TIMs from several LUSC metastatic models with inflammatory monocytes (IMs) of non-tumor-bearing controls. We identified Spon1 as upregulated in TIMs and found that Spon1 expression in LUSC tumors corresponded with poor survival and enrichment of collagen extracellular matrix signatures. We observed SPON1+ TIMs mediate their effects directly through LRP8 on NSCLC cells, which resulted in TGF-ß1 activation and robust production of fibrillar collagens. Using several orthogonal approaches, we demonstrated that SPON1+ TIMs were sufficient to promote NSCLC metastases. Additionally, we found that Spon1 loss in the host, or Lrp8 loss in cancer cells, resulted in a significant decrease of both high-density collagen matrices and metastases. Finally, we confirmed the relevance of the SPON1/LRP8/TGF-ß1 axis with collagen production and survival in patients with NSCLC. Taken together, our study describes how SPON1+ TIMs promote collagen remodeling and NSCLC metastases through an LRP8/TGF-ß1 signaling axis.
Sujet(s)
Carcinome pulmonaire non à petites cellules , Tumeurs du poumon , Monocytes , Transduction du signal , Animaux , Humains , Souris , Carcinome pulmonaire non à petites cellules/anatomopathologie , Carcinome pulmonaire non à petites cellules/métabolisme , Carcinome pulmonaire non à petites cellules/génétique , Carcinome pulmonaire non à petites cellules/secondaire , Lignée cellulaire tumorale , Collagène/métabolisme , Protéines de la matrice extracellulaire/métabolisme , Protéines de la matrice extracellulaire/génétique , Protéines apparentées au récepteur LDL/métabolisme , Protéines apparentées au récepteur LDL/génétique , Tumeurs du poumon/anatomopathologie , Tumeurs du poumon/métabolisme , Tumeurs du poumon/secondaire , Tumeurs du poumon/génétique , Monocytes/métabolisme , Monocytes/anatomopathologie , Métastase tumorale , Facteur de croissance transformant bêta-1/métabolismeRÉSUMÉ
The disassembly of the neuromuscular junction (NMJ) is an early event in amyotrophic lateral sclerosis (ALS), ultimately leading to motor dysfunction and lethal respiratory paralysis. The hexanucleotide GGGGCC repeat expansion in the C9orf72 gene is the most common genetic mutation, and the dipeptide repeat (DPR) proteins have been shown to cause neurodegeneration. While no drugs can treat ALS patients efficiently, new treatment strategies are urgently needed. Here, we report that a MuSK agonist antibody alleviates poly-PR-induced NMJ deficits in C9orf72-ALS mice. The HB9-PRF/F mice, which express poly-PR proteins in motor neurons, exhibited impaired motor behavior and NMJ deficits. Mechanistically, poly-PR proteins interacted with Agrin to disrupt the interaction between Agrin and Lrp4, leading to attenuated activation of MuSK. Treatment with a MuSK agonist antibody rescued NMJ deficits, and extended the lifespan of C9orf72-ALS mice. Moreover, impaired NMJ transmission was observed in C9orf72-ALS patients. These findings identify the mechanism by which poly-PR proteins attenuate MuSK activation and NMJ transmission, highlighting the potential of promoting MuSK activation with an agonist antibody as a therapeutic strategy to protect NMJ function and prolong the lifespan of ALS patients.
Sujet(s)
Sclérose latérale amyotrophique , Protéine C9orf72 , Modèles animaux de maladie humaine , Jonction neuromusculaire , Récepteurs à activité tyrosine kinase , Animaux , Jonction neuromusculaire/métabolisme , Jonction neuromusculaire/effets des médicaments et des substances chimiques , Souris , Sclérose latérale amyotrophique/génétique , Sclérose latérale amyotrophique/métabolisme , Sclérose latérale amyotrophique/traitement médicamenteux , Protéine C9orf72/génétique , Protéine C9orf72/métabolisme , Humains , Récepteurs à activité tyrosine kinase/métabolisme , Récepteurs à activité tyrosine kinase/génétique , Longévité/effets des médicaments et des substances chimiques , Motoneurones/métabolisme , Motoneurones/effets des médicaments et des substances chimiques , Agrine/métabolisme , Agrine/génétique , Souris transgéniques , Anticorps/pharmacologie , Récepteurs cholinergiques/métabolisme , Récepteurs cholinergiques/génétique , Protéines apparentées au récepteur LDL/métabolisme , Protéines apparentées au récepteur LDL/génétiqueRÉSUMÉ
In patients of Asian ancestry, a heterozygous CGG repeat expansion of >100 units in LRP12 is the cause of oculopharyngodistal myopathy type 1 (OPDM1). Repeat lengths of between 61 and 100 units have been associated with rare amyotrophic lateral sclerosis (ALS) cases of Asian ancestry, although with unusually long disease duration and without significant upper motor neuron involvement. This study sought to determine whether LRP12 CGG repeat expansions were also present in ALS patients of European ancestry. Whole-genome sequencing data from 608 sporadic ALS patients, 35 familial ALS probands, and 4703 neurologically normal controls were screened for LRP12 CGG expansions using ExpansionHunter v4. All individuals had LRP12 CGG repeat lengths within the normal range of 3-25 units. To date, LRP12 CGG repeat expansions have not been reported in ALS patients of European ancestry and may be limited to rare ALS patients of Asian ancestry and atypical clinical presentations.
Sujet(s)
Sclérose latérale amyotrophique , , Humains , Sclérose latérale amyotrophique/génétique , Mâle , Femelle , /génétique , Adulte d'âge moyen , Sujet âgé , Adulte , Protéines apparentées au récepteur LDL/génétique , Études de cohortes , Expansion de trinucléotide répété/génétiqueRÉSUMÉ
Selenium is an essential trace element that is delivered to the brain by the selenium transport protein selenoprotein P (SEPP1), primarily by binding to its receptor low-density lipoprotein receptor-related protein 8 (LRP8), also known as apolipoprotein E receptor 2 (ApoER2), at the blood-brain barrier. Selenium transport is required for several important brain functions, with transgenic deletion of either Sepp1 or Lrp8 resulting in severe neurological dysfunction and death in mice fed a selenium-deficient diet. Previous studies have reported that although feeding a standard chow diet can prevent these severe deficits, some motor coordination and cognitive dysfunction remain. Importantly, no single study has directly compared the motor and cognitive performance of the Sepp1 and Lrp8 knockout (KO) lines. Here, we report the results of a comprehensive parallel analysis of the motor and spatial learning and memory function of Sepp1 and Lrp8 knockout mice fed a standard mouse chow diet. Our results revealed that Sepp1 knockout mice raised on a selenium-replete diet displayed motor and cognitive function that was indistinguishable from their wild-type littermates. In contrast, we found that although Lrp8-knockout mice fed a selenium-replete diet had normal motor function, their spatial learning and memory showed subtle deficits. We also found that the deficit in baseline adult hippocampal neurogenesis exhibited by Lrp8-deficit mice could not be rescued by dietary selenium supplementation. Taken together, these findings further highlight the importance of selenium transport in maintaining healthy brain function. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
Sujet(s)
Protéines apparentées au récepteur LDL , Souris knockout , Sélénium , Apprentissage spatial , Animaux , Souris , Régime alimentaire , Hippocampe/métabolisme , Protéines apparentées au récepteur LDL/génétique , Protéines apparentées au récepteur LDL/métabolisme , Apprentissage du labyrinthe/physiologie , Apprentissage du labyrinthe/effets des médicaments et des substances chimiques , Mémoire/physiologie , Mémoire/effets des médicaments et des substances chimiques , Sélénium/administration et posologie , Sélénium/déficit , Sélénium/pharmacologie , Sélénoprotéine P/génétique , Sélénoprotéine P/métabolisme , Apprentissage spatial/physiologie , Apprentissage spatial/effets des médicaments et des substances chimiques , Mémoire spatiale/physiologie , Mémoire spatiale/effets des médicaments et des substances chimiquesRÉSUMÉ
Sortilin-related receptor 1 (SORL1) is an intracellular sorting receptor genetically implicated in Alzheimer's disease (AD) that impacts amyloid precursor protein trafficking. The objective of these studies was to test the hypothesis that SORL1 binds tau, modulates its cellular trafficking and impacts the aggregation of cytoplasmic tau induced by pathological forms of tau. Using surface plasmon resonance measurements, we observed high-affinity binding of tau to SORL1 and the vacuolar protein sorting 10 domain of SORL1. Interestingly, unlike LDL receptor-related protein 1, SORL1 binds tau at both pH 7.4 and pH 5.5, revealing its ability to bind tau at endosomal pH. Immunofluorescence studies confirmed that exogenously added tau colocalized with SORL1 in H4 neuroglioma cells, while overexpression of SORL1 in LDL receptor-related protein 1-deficient Chinese hamster ovary (CHO) cells resulted in a marked increase in the internalization of tau, indicating that SORL1 can bind and mediate the internalization of monomeric forms of tau. We further demonstrated that SORL1 mediates tau seeding when tau RD P301S FRET biosensor cells expressing SORL1 were incubated with high molecular weight forms of tau isolated from the brains of patients with AD. Seeding in H4 neuroglioma cells is significantly reduced when SORL1 is knocked down with siRNA. Finally, we demonstrate that the N1358S mutant of SORL1 significantly increases tau seeding when compared to WT SORL1, identifying for the first time a potential mechanism that connects this specific SORL1 mutation to Alzheimer's disease. Together, these studies identify SORL1 as a receptor that contributes to trafficking and seeding of pathogenic tau.
Sujet(s)
Cricetulus , Protéines apparentées au récepteur LDL , Protéines de transport membranaire , Protéines tau , Humains , Protéines tau/métabolisme , Protéines tau/génétique , Animaux , Cellules CHO , Protéines apparentées au récepteur LDL/métabolisme , Protéines apparentées au récepteur LDL/génétique , Protéines de transport membranaire/métabolisme , Protéines de transport membranaire/génétique , Maladie d'Alzheimer/métabolisme , Maladie d'Alzheimer/génétique , Maladie d'Alzheimer/anatomopathologie , Lignée cellulaire tumorale , Liaison aux protéines , Transport des protéinesRÉSUMÉ
Parkinson's disease (PD) is a highly prevalent and severe neurodegenerative disease that affects more than 10 million individuals worldwide. Pathogenic mutations in LRP10 have been associated with autosomal dominant PD. Here, we report an induced pluripotent stem cell (iPSC) line generated from a PD patient harboring the LRP10 c.688C > T (p.Arg230Trp) variant. Skin fibroblasts from the PD patient were successfully reprogrammed into iPSCs that expressed pluripotency markers, a normal karyotype, and the capacity to differentiate into the three germ layers in vivo. This iPSC line is a potential resource for studying the pathogenic mechanisms of PD.
Sujet(s)
Cellules souches pluripotentes induites , Mutation , Maladie de Parkinson , Cellules souches pluripotentes induites/métabolisme , Humains , Maladie de Parkinson/génétique , Maladie de Parkinson/anatomopathologie , Protéines apparentées au récepteur LDL/génétique , Protéines apparentées au récepteur LDL/métabolisme , Lignée cellulaire , Différenciation cellulaire , MâleRÉSUMÉ
SorLA, encoded by the gene SORL1, is an intracellular sorting receptor of the VPS10P domain receptor gene family. Although SorLA is best recognized for its ability to shuttle target proteins between intracellular compartments in neurons, recent data suggest that also its microglial expression can be of high relevance for the pathogenesis of brain diseases, including glioblastoma (GBM). Here, we interrogated the impact of SorLA on the functional properties of glioma-associated microglia and macrophages (GAMs). In the GBM microenvironment, GAMs are re-programmed and lose the ability to elicit anti-tumor responses. Instead, they acquire a glioma-supporting phenotype, which is a key mechanism promoting glioma progression. Our re-analysis of published scRNA-seq data from GBM patients revealed that functional phenotypes of GAMs are linked to the level of SORL1 expression, which was further confirmed using in vitro models. Moreover, we demonstrate that SorLA restrains secretion of TNFα from microglia to restrict the inflammatory potential of these cells. Finally, we show that loss of SorLA exacerbates the pro-inflammatory response of microglia in the murine model of glioma and suppresses tumor growth.
Sujet(s)
Tumeurs du cerveau , Gliome , Protéines apparentées au récepteur LDL , Protéines de transport membranaire , Microglie , Microenvironnement tumoral , Facteur de nécrose tumorale alpha , Animaux , Humains , Souris , Encéphale/métabolisme , Encéphale/anatomopathologie , Tumeurs du cerveau/métabolisme , Tumeurs du cerveau/anatomopathologie , Tumeurs du cerveau/génétique , Lignée cellulaire tumorale , Modèles animaux de maladie humaine , Glioblastome/métabolisme , Glioblastome/anatomopathologie , Glioblastome/génétique , Gliome/métabolisme , Gliome/anatomopathologie , Gliome/génétique , Macrophages/métabolisme , Protéines de transport membranaire/métabolisme , Protéines de transport membranaire/génétique , Microglie/métabolisme , Microglie/anatomopathologie , Facteur de nécrose tumorale alpha/métabolisme , Protéines apparentées au récepteur LDL/génétique , Protéines apparentées au récepteur LDL/métabolismeRÉSUMÉ
SORLA, the protein encoded by the SORL1 gene, has an important role in recycling cargo proteins to the cell surface. While SORLA loss-of-function variants occur almost exclusively in Alzheimer's disease cases, the majority of SORL1 variants are missense variants that are individually rare and can have individual mechanisms how they impair SORLA function as well as have individual effect size on disease risk. However, since carriers mostly come from small pedigrees, it is challenging to determine variant penetrance, leaving clinical significance associated with most missense variants unclear. In this article, we present functional approaches to evaluate the pathogenicity of a SORL1 variant, p.D1105H. First, we generated our mutant receptor by inserting the D1105H variant into the full-length SORLA-WT receptor. Then using western blot analysis we quantified the effect of the mutation on maturation and shedding of the receptor for transfected cells, and finally applied a flow cytometry approach to quantify SORLA expression at the cell surface. The results showed decreased maturation, decreased shedding, and decreased cell surface expression of D1105H compared with wild-type SORLA. We propose how these approaches can be used to functionally assess the pathogenicity of SORL1 variants in the future. This article is part of a discussion meeting issue 'Understanding the endo-lysosomal network in neurodegeneration'.
Sujet(s)
Maladie d'Alzheimer , Humains , Virulence , Mutation , Maladie d'Alzheimer/génétique , Prédisposition génétique à une maladie , Protéines apparentées au récepteur LDL/génétique , Protéines apparentées au récepteur LDL/métabolisme , Protéines de transport membranaire/génétiqueRÉSUMÉ
Adaptor protein complex 4 (AP-4) is a heterotetrameric complex that promotes export of selected cargo proteins from the trans-Golgi network. Mutations in each of the AP-4 subunits cause a complicated form of Hereditary Spastic Paraplegia (HSP). Herein, we report that ApoER2, a receptor in the Reelin signaling pathway, is a cargo of the AP-4 complex. We identify the motif ISSF/Y within the ApoER2 cytosolic domain as necessary for interaction with the canonical signal-binding pocket of the µ4 (AP4M1) subunit of AP-4. AP4E1- knock-out (KO) HeLa cells and hippocampal neurons from Ap4e1-KO mice display increased co-localization of ApoER2 with Golgi markers. Furthermore, hippocampal neurons from Ap4e1-KO mice and AP4M1-KO human iPSC-derived cortical i3Neurons exhibit reduced ApoER2 protein expression. Analyses of biosynthetic transport of ApoER2 reveal differential post-Golgi trafficking of the receptor, with lower axonal distribution in KO compared to wild-type neurons, indicating a role of AP-4 and the ISSF/Y motif in the axonal localization of ApoER2. Finally, analyses of Reelin signaling in mouse hippocampal and human cortical KO neurons show that AP4 deficiency causes no changes in Reelin-dependent activation of the AKT pathway and only mild changes in Reelin-induced dendritic arborization, but reduces Reelin-induced ERK phosphorylation, CREB activation, and Golgi deployment. This work thus establishes ApoER2 as a novel cargo of the AP-4 complex, suggesting that defects in the trafficking of this receptor and in the Reelin signaling pathway could contribute to the pathogenesis of HSP caused by mutations in AP-4 subunits.
Sujet(s)
Complexe protéique adaptateur 4 , Protéines apparentées au récepteur LDL , Paraplégie spasmodique héréditaire , Animaux , Humains , Souris , Complexe protéique adaptateur 4/génétique , Complexe protéique adaptateur 4/métabolisme , Cellules HeLa , Protéines apparentées au récepteur LDL/génétique , Protéines apparentées au récepteur LDL/métabolisme , Récepteurs de surface cellulaire , Paraplégie spasmodique héréditaire/génétique , Paraplégie spasmodique héréditaire/métabolismeRÉSUMÉ
The SORL1 gene has recently emerged as a strong Alzheimer's Disease (AD) risk gene. Over 500 different variants have been identified in the gene and the contribution of individual variants to AD development and progression is still largely unknown. Here, we describe a family consisting of 2 parents and 5 offspring. Both parents were affected with dementia and one had confirmed AD pathology with an age of onset > 75 years. All offspring were affected with AD with ages at onset ranging from 53 years to 74 years. DNA was available from the parent with confirmed AD and 5 offspring. We identified a coding variant, p.(Arg953Cys), in SORL1 in 5 of 6 individuals affected by AD. Notably, variant carriers had severe AD pathology, and the SORL1 variant segregated with TDP-43 pathology (LATE-NC). We further characterized this variant and show that this Arginine substitution occurs at a critical position in the YWTD-domain of the SORL1 translation product, SORL1. Functional studies further show that the p.R953C variant leads to retention of the SORL1 protein in the endoplasmic reticulum which leads to decreased maturation and shedding of the receptor and prevents its normal endosomal trafficking. Together, our analysis suggests that p.R953C is a pathogenic variant of SORL1 and sheds light on mechanisms of how missense SORL1 variants may lead to AD.
Sujet(s)
Maladie d'Alzheimer , Humains , Sujet âgé , Maladie d'Alzheimer/génétique , Fréquence d'allèle , Prédisposition génétique à une maladie , Protéines de transport membranaire/génétique , Mutation faux-sens , Protéines apparentées au récepteur LDL/génétique , Polymorphisme de nucléotide simpleRÉSUMÉ
OBJECTIVE: In Norway, 89% of patients with Amyotrophic lateral sclerosis (ALS) lacks a genetic diagnose. ALS genes and genes that cause other neuromuscular or neurodegenerative disorders extensively overlap. This population-based study examined whether patients with ALS have a family history of neurological disorders and explored the occurrence of rare genetic variants associated with other neurodegenerative or neuromuscular disorders. METHODS: During a two-year period, blood samples and clinical data from patients with ALS were collected from all 17 neurological departments in Norway. Our genetic analysis involved exome sequencing and bioinformatics filtering of 510 genes associated with neurodegenerative and neuromuscular disorders. The variants were interpreted using genotype-phenotype correlations and bioinformatics tools. RESULTS: A total of 279 patients from a Norwegian population-based ALS cohort participated in this study. Thirty-one percent of the patients had first- or second-degree relatives with other neurodegenerative disorders, most commonly dementia and Parkinson's disease. The genetic analysis identified 20 possible pathogenic variants, in ATL3, AFG3L2, ATP7A, BICD2, HARS1, KIF1A, LRRK2, MSTO1, NEK1, NEFH, and SORL1, in 25 patients. NEK1 risk variants were present in 2.5% of this ALS cohort. Only four of the 25 patients reported relatives with other neurodegenerative or neuromuscular disorders. CONCLUSION: Gene variants known to cause other neurodegenerative or neuromuscular disorders, most frequently in NEK1, were identified in 9% of the patients with ALS. Most of these patients had no family history of other neurodegenerative or neuromuscular disorders. Our findings indicated that AFG3L2, ATP7A, BICD2, KIF1A, and MSTO1 should be further explored as potential ALS-causing genes.
Sujet(s)
Sclérose latérale amyotrophique , Protéines du cycle cellulaire , Maladies neurodégénératives , Humains , Prédisposition génétique à une maladie/génétique , Sclérose latérale amyotrophique/épidémiologie , Sclérose latérale amyotrophique/génétique , Études d'associations génétiques , Famille , Maladies neurodégénératives/épidémiologie , Maladies neurodégénératives/génétique , ATPases associated with diverse cellular activities/génétique , ATP-dependent proteases/génétique , Protéines apparentées au récepteur LDL/génétique , Protéines de transport membranaire/génétique , Kinésine/génétique , Protéines du cytosquelette/génétiqueRÉSUMÉ
Pathogenic variants disrupting the binding between sclerostin (encoded by SOST) and its receptor LRP4 have previously been described to cause sclerosteosis, a rare high bone mass disorder. The sclerostin-LRP4 complex inhibits canonical WNT signaling, a key pathway regulating osteoblastic bone formation and a promising therapeutic target for common bone disorders, such as osteoporosis. In the current study, we crossed mice deficient for Sost (Sost-/-) with our p.Arg1170Gln Lrp4 knock-in (Lrp4KI/KI) mouse model to create double mutant Sost-/-;Lrp4KI/KI mice. We compared the phenotype of Sost-/- mice with that of Sost-/-;Lrp4KI/KI mice, to investigate a possible synergistic effect of the disease-causing p.Arg1170Trp variant in Lrp4 on Sost deficiency. Interestingly, presence of Lrp4KI alleles partially mitigated the Sost-/- phenotype. Cellular and dynamic histomorphometry did not reveal mechanistic insights into the observed phenotypic differences. We therefore determined the molecular effect of the Lrp4KI allele by performing bulk RNA sequencing on Lrp4KI/KI primary osteoblasts. Unexpectedly, mostly genes related to bone resorption or remodeling (Acp5, Rankl, Mmp9) were upregulated in Lrp4KI/KI primary osteoblasts. Verification of these markers in Lrp4KI/KI, Sost-/- and Sost-/-;Lrp4KI/KI mice revealed that sclerostin deficiency counteracts this Lrp4KI/KI effect in Sost-/-;Lrp4KI/KI mice. We therefore hypothesize that models with two inactivating Lrp4KI alleles rather activate bone remodeling, with a net gain in bone mass, whereas sclerostin deficiency has more robust anabolic effects on bone formation. Moreover, these effects of sclerostin and Lrp4 are stronger in female mice, contributing to a more severe phenotype than in males and more detectable phenotypic differences among different genotypes.
Sujet(s)
Protéines adaptatrices de la transduction du signal , Remodelage osseux , Hyperostose , Syndactylie , Mâle , Femelle , Animaux , Souris , Protéines adaptatrices de la transduction du signal/génétique , Protéines adaptatrices de la transduction du signal/métabolisme , Souris knockout , Phénotype , Mutation , Remodelage osseux/génétique , Protéines apparentées au récepteur LDL/génétique , Protéines apparentées au récepteur LDL/métabolismeRÉSUMÉ
BACKGROUND: Cenani-Lenzsyndactyly syndrome (CLSS; OMIM 212780) is a rare autosomal recessive acral deformity, which is mainly manifested in the fusion of fingers or toes, disordered phalangeal structure, shortening or fusion of the radius and ulna, and renal hypoplasia. CASE PRESENTATION: Our report described an individual with mild phenotypes from China. His parents were not consanguineous. The affected individual was non-dysmorphic. Standard X-ray showed that the both hands have only four metacarpal bones. The distal end of the first metacarpal bone on the right was relatively slender, and the distal phalanx was absent. Multiple phalanges and some soft tissues of both hands were fused. Exome sequencing revealed a novel biallelic c.282C⟩Avariant in low-density lipoprotein receptor-related protein 4 (LRP4; OMIM604270; NM_002334.4) causing p. (Asn94Lys) change in the encoded protein. This variant is predicted to be potentially pathogenic, affecting protein structure and function. CONCLUSION: We report a novel missense variant present in homozygosity in LRP4 to broaden the pathogenic spectrum of LRP4 in syndactyly, and exome sequencing technology is a powerful tool for genetic analysis in prenatal diagnosis and medical research, as a preferred method for the diagnosis of syndactyly and related phenotypes.
Sujet(s)
Protéines apparentées au récepteur LDL , Syndactylie , Humains , Mutation , Protéines apparentées au récepteur LDL/génétique , Protéines apparentées au récepteur LDL/métabolisme , Syndactylie/génétique , Syndactylie/diagnostic , Mutation faux-sensRÉSUMÉ
LRP4 is expressed in many organs. It mediates SOST-dependent inhibition of bone formation and acts as an inhibitor of WNT signaling. It is also a postsynaptic end plate cell surface receptor at the neuromuscular junction and is central to its development, maintenance, and function. Pathogenic variants of LRP4 that specifically affect the canonical WNT signaling pathway are known to be associated with Cenani-Lenz syndactyly syndrome or the overlapping condition sclerosteosis. However, site-specific pathogenic variants of LRP4 have been associated with the congenital myasthenic syndrome (CMS) type 17 with no abnormal bone phenotype. Only two studies reported biallelic variants of LRP4 associated with CMS17 that presented during childhood. All three reported variants (NM_002334.4: p.Glu1233Ala, p.Glu1233Lys, or p.Arg1277His) are located within the 3'-edge of the third ß-propeller domain of LRP4. We report on a patient with a biallelic variant of the LRP4 gene presenting with a severe and neonatal lethal phenotype; we also provide a literature review of the previously reported patients. A female neonate, born to healthy consanguineous parents, presented with severe hypotonia, congenital diaphragmatic hernia, pulmonary hypertension, and progressive hypoxemia. Two of her siblings presented with a similar condition in the past, and all three died shortly after birth. Clinical exome sequencing revealed homozygosity for the pathogenic variant NM_002334.4:c.3698A > C (p.[Glu1233Ala]).
Sujet(s)
Hyperostose , Syndromes myasthéniques congénitaux , Syndactylie , Femelle , Humains , Nouveau-né , Protéines apparentées au récepteur LDL/génétique , Syndromes myasthéniques congénitaux/génétique , Jonction neuromusculaire , Syndactylie/génétique , MâleRÉSUMÉ
The SORL1 gene (SORLA) is strongly associated with risk of developing Alzheimer's disease (AD). SORLA is a regulator of endosomal trafficking in neurons and interacts with retromer, a complex that is a "master conductor" of endosomal trafficking. Small molecules can increase retromer expression in vitro, enhancing its function. We treated hiPSC-derived cortical neurons that are either fully deficient, haploinsufficient, or that harbor one copy of SORL1 variants linked to AD with TPT-260, a retromer-enhancing molecule. We show significant increases in retromer subunit VPS26B expression. We tested whether endosomal, amyloid, and TAU pathologies were corrected. We observed that the degree of rescue by TPT-260 treatment depended on the number of copies of functional SORL1 and which SORL1 variant was expressed. Using a disease-relevant preclinical model, our work illuminates how the SORL1-retromer pathway can be therapeutically harnessed.
Sujet(s)
Maladie d'Alzheimer , Protéines apparentées au récepteur LDL , Protéines de transport membranaire , Humains , Maladie d'Alzheimer/génétique , Maladie d'Alzheimer/métabolisme , Endosomes/métabolisme , Cellules souches pluripotentes induites/effets des médicaments et des substances chimiques , Cellules souches pluripotentes induites/métabolisme , Protéines apparentées au récepteur LDL/génétique , Protéines apparentées au récepteur LDL/métabolisme , Protéines de transport membranaire/génétique , Protéines de transport membranaire/métabolisme , Neurones/métabolismeRÉSUMÉ
A family of Pakistani origin, segregating polydactyly, and phalangeal synostosis in an autosomal dominant manner, has been investigated and presented in the present report. Whole-exome sequencing (WES), followed by segregation analysis using Sanger sequencing, revealed a heterozygous missense variant [c.G1696A, p.(Gly566Ser)] in the LRP4 gene located on human chromosome 11p11.2. Homology protein modeling revealed the mutant Ser566 generated new interactions with at least four other amino acids and disrupted protein folding and function. Our findings demonstrated the first direct evidence of involvement of LRP4 in causing polydactyly and phalangeal synostosis in the same family. This study highlighted the importance of inclusion of LRP4 gene in screening individuals presenting polydactyly in hands and feet, and phalangeal synostosis in the same family.