8 results on '"Bai, Ge"'
Search Results
2. Diverse CMT2 neuropathies are linked to aberrant G3BP interactions in stress granules.
- Author
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Cui Q, Bi H, Lv Z, Wu Q, Hua J, Gu B, Huo C, Tang M, Chen Y, Chen C, Chen S, Zhang X, Wu Z, Lao Z, Sheng N, Shen C, Zhang Y, Wu ZY, Jin Z, Yang P, Liu H, Li J, and Bai G
- Subjects
- Animals, Mice, Cytoplasm, Motor Neurons, Charcot-Marie-Tooth Disease genetics, Charcot-Marie-Tooth Disease metabolism, Charcot-Marie-Tooth Disease pathology, Stress Granules, RNA Recognition Motif Proteins metabolism
- Abstract
Complex diseases often involve the interplay between genetic and environmental factors. Charcot-Marie-Tooth type 2 neuropathies (CMT2) are a group of genetically heterogeneous disorders, in which similar peripheral neuropathology is inexplicably caused by various mutated genes. Their possible molecular links remain elusive. Here, we found that upon environmental stress, many CMT2-causing mutant proteins adopt similar properties by entering stress granules (SGs), where they aberrantly interact with G3BP and integrate into SG pathways. For example, glycyl-tRNA synthetase (GlyRS) is translocated from the cytoplasm into SGs upon stress, where the mutant GlyRS perturbs the G3BP-centric SG network by aberrantly binding to G3BP. This disrupts SG-mediated stress responses, leading to increased stress vulnerability in motoneurons. Disrupting this aberrant interaction rescues SG abnormalities and alleviates motor deficits in CMT2D mice. These findings reveal a stress-dependent molecular link across diverse CMT2 mutants and provide a conceptual framework for understanding genetic heterogeneity in light of environmental stress., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)
- Published
- 2023
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3. Identification and functional characterization of novel GDAP1 variants in Chinese patients with Charcot-Marie-Tooth disease.
- Author
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Chen CX, Li JQ, Dong HL, Liu GL, Bai G, and Wu ZY
- Subjects
- Adult, Aged, Child, Preschool, China, Female, Humans, Male, Pedigree, Exome Sequencing, Charcot-Marie-Tooth Disease genetics, Nerve Tissue Proteins genetics, Sequence Analysis, DNA
- Abstract
Objective: To identify and characterize the pathogenicity of novel variants in Chinese patients with Charcot-Marie-Tooth disease., Methods: Multiplex ligation-dependent probe amplification (MLPA) and whole-exome sequencing (WES) were performed in 30 unrelated CMT patients. Minigene assay was used to verify the effect of a novel splicing variant (c.694+1G>A) on pre-mRNA. Primary fibroblast cell lines were established from skin biopsies to characterize the biological effects of the novel variants p.L26R and p.S169fs. The mitochondrial structure was observed by an electron microscope. The expression level of protein was analyzed by Western Blotting. Mitochondrial dynamics and mitochondrial membrane potential (MMP, Δψm) were analyzed via immunofluorescence study. Mitochondrial ATP levels were analyzed via bioluminescence assay. The rate of oxygen consumption was measured with a Seahorse Bioscience XF-96 extracellular flux analyzer., Results: We identified 10 pathogenic variants in three known CMT related genes, including three novel variants (p.L26R, p.S169fs, c.694+1G>A) and one known pathogenic variant (p.R120W) in GDAP1. Further, we described the clinical features of patients carrying pathogenic variants in GDAP1 and found that almost all Chinese CMT patients with GDAP1 variants present axonal type. The effect of c.694+1G>A on pre-mRNA was verified via minigene splice assay. Cellular biological effects showed ultrastructure damage of mitochondrial, reduced protein levels, different patterns of mitochondrial dynamics, decreased mitochondrial membrane potential (Δψm), ATP content, and defects in respiratory capacity in the patient carrying p.L26R and p.S169fs in GDAP1., Interpretation: Our results broaden the genetic spectrum of GDAP1 and provided functional evidence for mitochondrial pathways in the pathogenesis of GDAP1 variants., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)
- Published
- 2020
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4. Genetic spectrum of MCM3AP and its relationship with phenotype of Charcot-Marie-Tooth disease.
- Author
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Dong HL, Wei Q, Li JQ, Li HF, Bai G, Ma H, and Wu ZY
- Subjects
- Child, Female, Humans, Pedigree, Phenotype, Acetyltransferases genetics, Charcot-Marie-Tooth Disease genetics, Charcot-Marie-Tooth Disease physiopathology, Intracellular Signaling Peptides and Proteins genetics
- Abstract
Mutations in MCM3AP have recently been reported to cause autosomal recessive Charcot-Marie-Tooth disease (CMT). However, only nine CMT families with MCM3AP mutations have been reported and genotype-phenotype correlation remains unclear. This study aimed to investigate the genetic spectrum of MCM3AP and its relationship with phenotype of CMT. Whole-exome sequencing (WES) was performed in the family and variants were validated by Sanger sequencing. Reverse transcription-PCR (RT-PCR) were performed in splicing analysis. We reported a novel splicing variant (c.5634-1G>T) and a known missense variant (c.2633G>A, p.Arg878His). Functional studies showed that c.5634-1G>T led to splicing defect and aberrant transcript eliminated by nonsense-mediated mRNA decay. The symptom of the patient was less severe and slowly progressed with axonal peripheral neuropathy compared to the reported CMT patients. Genotype-phenotype correlation analysis indicated that affected individuals with null mutations presented with delayed independent walking. The percentage of intellectual disability and loss of ambulation in the null group tended to be greater, although this failed to reach statistical significance. Our findings expand the genetic spectrum of MCM3AP and suggest that genotype-phenotype correlation would help genetic counseling of MCM3AP in CMT patients., (© 2020 Peripheral Nerve Society.)
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- 2020
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5. Genetic spectrum and clinical profiles in a southeast Chinese cohort of Charcot-Marie-Tooth disease.
- Author
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Chen CX, Dong HL, Wei Q, Li LX, Yu H, Li JQ, Liu GL, Li HF, Bai G, Ma H, and Wu ZY
- Subjects
- Adolescent, Adult, Age of Onset, Charcot-Marie-Tooth Disease epidemiology, Charcot-Marie-Tooth Disease pathology, Child, Child, Preschool, China epidemiology, Female, Gene Rearrangement genetics, Genotype, Humans, Infant, Male, Middle Aged, Mutation genetics, Sequence Deletion genetics, Young Adult, Charcot-Marie-Tooth Disease genetics, High-Throughput Nucleotide Sequencing, Myelin Proteins genetics
- Abstract
Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of inherited sensorimotor neuropathies. To clarify the genetic spectrum and clinical profiles in Chinese CMT patients, we enrolled 150 unrelated CMT patients from southeast China. We performed multiplex ligation-dependent probe amplification (MLPA) testing in all patients and next-generation sequencing (NGS) among those patients without PMP22 rearrangements. We identified PMP22 duplications in 40 patients and deletions in 12 patients. In addition, we found 19 novel variants and 36 known mutations in 57 patients. Among these 55 variants, 45 pathogenic or likely pathogenic variants were identified in 48 cases, and 10 variants with uncertain significance were identified in 9 cases. Therefore, we obtained a genetic diagnosis in 63.8% (88/138) of CMT patients and 66.7% (100/150) of all included patients. PMP22, GJB1, and MFN2 are the most common causative genes in CMT1 (demyelinated form), intermediate CMT, and CMT2 (axonal form), respectively. In this study, we identified a higher proportion of intermediate CMT, a relatively high frequency of NDRG1 mutations and clinical features of later onset age in CMT1A patients. Our results broaden the genetic and clinical spectrum of CMT patients, which can help optimize the genetic and clinical diagnosis., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2019
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6. Aberrant GlyRS-HDAC6 interaction linked to axonal transport deficits in Charcot-Marie-Tooth neuropathy.
- Author
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Mo Z, Zhao X, Liu H, Hu Q, Chen XQ, Pham J, Wei N, Liu Z, Zhou J, Burgess RW, Pfaff SL, Caskey CT, Wu C, Bai G, and Yang XL
- Subjects
- Acetylation, Animals, Axonal Transport drug effects, Charcot-Marie-Tooth Disease genetics, Disease Models, Animal, Female, Glycine-tRNA Ligase genetics, HEK293 Cells, Histone Deacetylase 6 antagonists & inhibitors, Humans, Hydroxamic Acids pharmacology, Indoles pharmacology, Male, Mice, Mice, Inbred C57BL, Mutation, Nerve Tissue Proteins metabolism, Neuropilin-1 metabolism, Peripheral Nerves metabolism, Tubulin metabolism, Axonal Transport genetics, Axons metabolism, Charcot-Marie-Tooth Disease pathology, Glycine-tRNA Ligase metabolism, Histone Deacetylase 6 metabolism, Motor Neurons metabolism
- Abstract
Dominant mutations in glycyl-tRNA synthetase (GlyRS) cause a subtype of Charcot-Marie-Tooth neuropathy (CMT2D). Although previous studies have shown that GlyRS mutants aberrantly interact with Nrp1, giving insight into the disease's specific effects on motor neurons, these cannot explain length-dependent axonal degeneration. Here, we report that GlyRS mutants interact aberrantly with HDAC6 and stimulate its deacetylase activity on α-tubulin. A decrease in α-tubulin acetylation and deficits in axonal transport are observed in mice peripheral nerves prior to disease onset. An HDAC6 inhibitor used to restore α-tubulin acetylation rescues axonal transport deficits and improves motor functions of CMT2D mice. These results link the aberrant GlyRS-HDAC6 interaction to CMT2D pathology and suggest HDAC6 as an effective therapeutic target. Moreover, the HDAC6 interaction differs from Nrp1 interaction among GlyRS mutants and correlates with divergent clinical presentations, indicating the existence of multiple and different mechanisms in CMT2D.
- Published
- 2018
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7. Alternative stable conformation capable of protein misinteraction links tRNA synthetase to peripheral neuropathy.
- Author
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Blocquel D, Li S, Wei N, Daub H, Sajish M, Erfurth ML, Kooi G, Zhou J, Bai G, Schimmel P, Jordanova A, and Yang XL
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- Amino Acid Substitution, Crystallography, X-Ray, Deuterium Exchange Measurement, Enzyme Stability genetics, Humans, Kinetics, Models, Molecular, Mutant Proteins chemistry, Mutant Proteins genetics, Mutant Proteins metabolism, Protein Binding, Protein Conformation, Protein Folding, Protein Multimerization genetics, Recombinant Proteins chemistry, Recombinant Proteins genetics, Recombinant Proteins metabolism, Repressor Proteins metabolism, Scattering, Small Angle, Tripartite Motif-Containing Protein 28, Tyrosine-tRNA Ligase genetics, X-Ray Diffraction, Charcot-Marie-Tooth Disease enzymology, Charcot-Marie-Tooth Disease genetics, Tyrosine-tRNA Ligase chemistry, Tyrosine-tRNA Ligase metabolism
- Abstract
While having multiple aminoacyl-tRNA synthetases implicated in Charcot-Marie-Tooth (CMT) disease suggests a common mechanism, a defect in enzymatic activity is not shared among the CMT-causing mutants. Protein misfolding is a common hypothesis underlying the development of many neurological diseases. Its process usually involves an initial reduction in protein stability and then the subsequent oligomerization and aggregation. Here, we study the structural effect of three CMT-causing mutations in tyrosyl-tRNA synthetase (TyrRS or YARS). Through various approaches, we found that the mutations do not induce changes in protein secondary structures, or shared effects on oligomerization state and stability. However, all mutations provide access to a surface masked in the wild-type enzyme, and that access correlates with protein misinteraction. With recent data on another CMT-linked tRNA synthetase, we suggest that an inherent plasticity, engendering the formation of alternative stable conformations capable of aberrant interactions, links the tRNA synthetase family to CMT., (© The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.)
- Published
- 2017
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8. CMT2D neuropathy is linked to the neomorphic binding activity of glycyl-tRNA synthetase.
- Author
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He W, Bai G, Zhou H, Wei N, White NM, Lauer J, Liu H, Shi Y, Dumitru CD, Lettieri K, Shubayev V, Jordanova A, Guergueltcheva V, Griffin PR, Burgess RW, Pfaff SL, and Yang XL
- Subjects
- Animals, Axons enzymology, Axons metabolism, Axons pathology, Cell Line, Cell Survival, Charcot-Marie-Tooth Disease drug therapy, Charcot-Marie-Tooth Disease genetics, Charcot-Marie-Tooth Disease pathology, Female, Glycine-tRNA Ligase chemistry, Glycine-tRNA Ligase genetics, Ligands, Male, Mice, Models, Molecular, Motor Neurons enzymology, Motor Neurons metabolism, Motor Neurons pathology, Motor Skills drug effects, Mutation genetics, Neuropilin-1 deficiency, Neuropilin-1 genetics, Neuropilin-1 metabolism, Protein Binding, Protein Multimerization, Signal Transduction, Vascular Endothelial Growth Factor A metabolism, Vascular Endothelial Growth Factor A pharmacology, Vascular Endothelial Growth Factor A therapeutic use, Binding, Competitive, Charcot-Marie-Tooth Disease metabolism, Glycine-tRNA Ligase metabolism
- Abstract
Selective neuronal loss is a hallmark of neurodegenerative diseases, which, counterintuitively, are often caused by mutations in widely expressed genes. Charcot-Marie-Tooth (CMT) diseases are the most common hereditary peripheral neuropathies, for which there are no effective therapies. A subtype of these diseases--CMT type 2D (CMT2D)--is caused by dominant mutations in GARS, encoding the ubiquitously expressed enzyme glycyl-transfer RNA (tRNA) synthetase (GlyRS). Despite the broad requirement of GlyRS for protein biosynthesis in all cells, mutations in this gene cause a selective degeneration of peripheral axons, leading to deficits in distal motor function. How mutations in GlyRS (GlyRS(CMT2D)) are linked to motor neuron vulnerability has remained elusive. Here we report that GlyRS(CMT2D) acquires a neomorphic binding activity that directly antagonizes an essential signalling pathway for motor neuron survival. We find that CMT2D mutations alter the conformation of GlyRS, enabling GlyRS(CMT2D) to bind the neuropilin 1 (Nrp1) receptor. This aberrant interaction competitively interferes with the binding of the cognate ligand vascular endothelial growth factor (VEGF) to Nrp1. Genetic reduction of Nrp1 in mice worsens CMT2D symptoms, whereas enhanced expression of VEGF improves motor function. These findings link the selective pathology of CMT2D to the neomorphic binding activity of GlyRS(CMT2D) that antagonizes the VEGF-Nrp1 interaction, and indicate that the VEGF-Nrp1 signalling axis is an actionable target for treating CMT2D.
- Published
- 2015
- Full Text
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