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14. Microglial pattern recognition via IL-33 promotes synaptic refinement in developing corticothalamic circuits in mice

Author

Han, Rafael T, Vainchtein, Ilia D, Schlachetzki, Johannes CM, Cho, Frances S, Dorman, Leah C, Ahn, Eunji, Kim, Dong Kyu, Barron, Jerika J, Nakao-Inoue, Hiromi, Molofsky, Ari B, Glass, Christopher K, Paz, Jeanne T, and Molofsky, Anna V

Subjects
Biomedical and Clinical Sciences, Neurosciences, Brain Disorders, Pediatric, Genetics, Aetiology, 2.1 Biological and endogenous factors, Neurological, Animals, Mice, Microglia, Interleukin-33, Synapses, Brain, Seizures, Mice, Inbred C57BL, Medical and Health Sciences, Immunology, Biomedical and clinical sciences, Health sciences
Abstract

Microglia are critical regulators of brain development that engulf synaptic proteins during postnatal synapse remodeling. However, the mechanisms through which microglia sense the brain environment are not well defined. Here, we characterized the regulatory program downstream of interleukin-33 (IL-33), a cytokine that promotes microglial synapse remodeling. Exposing the developing brain to a supraphysiological dose of IL-33 altered the microglial enhancer landscape and increased binding of stimulus-dependent transcription factors including AP-1/FOS. This induced a gene expression program enriched for the expression of pattern recognition receptors, including the scavenger receptor MARCO. CNS-specific deletion of IL-33 led to increased excitatory/inhibitory synaptic balance, spontaneous absence-like epileptiform activity in juvenile mice, and increased seizure susceptibility in response to chemoconvulsants. We found that MARCO promoted synapse engulfment, and Marco-deficient animals had excess thalamic excitatory synapses and increased seizure susceptibility. Taken together, these data define coordinated epigenetic and functional changes in microglia and uncover pattern recognition receptors as potential regulators of postnatal synaptic refinement.

Published
2023

24. TNF-α promotes α-synuclein propagation through stimulation of senescence-associated lysosomal exocytosis.

Author

Bae, Eun-Jin, Choi, Minsun, Kim, Jeong, Kim, Dong-Kyu, Jung, Min, Kim, Changyoun, Kim, Tae-Kyung, Lee, Jun, Jung, Byung, Shin, Soo, Rhee, Ka, and Lee, Seung-Jae

Subjects
Exocytosis, Humans, Inflammation, Lysosomes, Tumor Necrosis Factor-alpha, alpha-Synuclein
Abstract

Cell-to-cell propagation of α-synuclein is thought to be the underlying mechanism of Parkinsons disease progression. Recent evidence suggests that inflammation plays an important role in the propagation of protein aggregates. However, the mechanism by which inflammation regulates the propagation of aggregates remains unknown. Here, using in vitro cultures, we found that soluble factors secreted from activated microglia promote cell-to-cell propagation of α-synuclein and further showed that among these soluble factors, TNF-α had the most robust stimulatory activity. Treatment of neurons with TNF-α triggered cellular senescence, as shown by transcriptomic analyses demonstrating induction of senescence-associated genes and immunoanalysis of senescence phenotype marker proteins. Interestingly, secretion of α-synuclein was increased in senescent neurons, reflecting acquisition of a senescence-associated secretory phenotype (SASP). Using vacuolin-1, an inhibitor of lysosomal exocytosis, and RNAi against rab27a, we demonstrated that the SASP was mediated by lysosomal exocytosis. Correlative light and electron microscopy and immunoelectron microscopy confirmed that propagating α-synuclein aggregates were present in electron-dense lysosome-like compartments. TNF-α promoted the SASP through stimulation of lysosomal exocytosis, thereby increasing the secretion of α-synuclein. Collectively, these results suggest that TNF-α is the major inflammatory factor that drives cell-to-cell propagation of α-synuclein by promoting the SASP and subsequent secretion of α-synuclein.

Published
2022

36. Type-I-interferon-responsive microglia shape cortical development and behavior

Author

Escoubas, Caroline C., Dorman, Leah C., Nguyen, Phi T., Lagares-Linares, Christian, Nakajo, Haruna, Anderson, Sarah R., Barron, Jerika J., Wade, Sarah D., Cuevas, Beatriz, Vainchtein, Ilia D., Silva, Nicholas J., Guajardo, Ricardo, Xiao, Yinghong, Lidsky, Peter V., Wang, Ellen Y., Rivera, Brianna M., Taloma, Sunrae E., Kim, Dong Kyu, Kaminskaya, Elizaveta, Nakao-Inoue, Hiromi, Schwer, Bjoern, Arnold, Thomas D., Molofsky, Ari B., Condello, Carlo, Andino, Raul, Nowakowski, Tomasz J., and Molofsky, Anna V.

Published
2024
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44. Structural basis for the dynamics of human methionyl-tRNA synthetase in multi-tRNA synthetase complexes

Author

Kim, Dong Kyu, Lee, Hyun Joo, Kong, Jiwon, Cho, Ha Yeon, Kim, Sunghoon, and Kang, Beom Sik

Subjects
Biochemistry and Cell Biology, Chemical Sciences, Biological Sciences, Generic health relevance, Binding Sites, Catalytic Domain, Crystallography, X-Ray, Humans, Methionine-tRNA Ligase, Models, Molecular, Peptide Elongation Factors, Peptides, Protein Conformation, RNA, Transfer, Tumor Suppressor Proteins, Zinc, Environmental Sciences, Information and Computing Sciences, Developmental Biology, Biological sciences, Chemical sciences, Environmental sciences
Abstract

In mammals, eight aminoacyl-tRNA synthetases (AARSs) and three AARS-interacting multifunctional proteins (AIMPs) form a multi-tRNA synthetase complex (MSC). MSC components possess extension peptides for MSC assembly and specific functions. Human cytosolic methionyl-tRNA synthetase (MRS) has appended peptides at both termini of the catalytic main body. The N-terminal extension includes a glutathione transferase (GST) domain responsible for interacting with AIMP3, and a long linker peptide between the GST and catalytic domains. Herein, we determined crystal structures of the human MRS catalytic main body, and the complex of the GST domain and AIMP3. The structures reveal human-specific structural details of the MRS, and provide a dynamic model for MRS at the level of domain orientation. A movement of zinc knuckles inserted in the catalytic domain is required for MRS catalytic activity. Depending on the position of the GST domain relative to the catalytic main body, MRS can either block or present its tRNA binding site. Since MRS is part of a huge MSC, we propose a dynamic switching between two possible MRS conformations; a closed conformation in which the catalytic domain is compactly attached to the MSC, and an open conformation with a free catalytic domain dissociated from other MSC components.

Published
2021

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