دورية أكاديمية
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Toll-like receptor 4 deficiency in Purkinje neurons drives cerebellar ataxia by impairing the BK channel-mediated after-hyperpolarization and cytosolic calcium homeostasis.

التفاصيل البيبلوغرافية
العنوان: Toll-like receptor 4 deficiency in Purkinje neurons drives cerebellar ataxia by impairing the BK channel-mediated after-hyperpolarization and cytosolic calcium homeostasis.
المؤلفون: Zhu J; Department of Neurosurgery, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China., Qiu W; Department of Neurosurgery, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China., Wei F; Department of Neurosurgery, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China.; Department of Critical Care Medicine, Mianyang Orthopaedic Hospital, Mianyang, Sichuan Province, 621000, China., Zhang J; Department of Neurosurgery, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China., Yuan Y; Department of Neurosurgery, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China., Liu L; Department of Neurosurgery, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China., Cheng M; Department of Neurosurgery, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China., Xiong H; Department of Neurosurgery, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China. huan_xiong@163.com., Xu R; Department of Neurosurgery, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China. xuruxiang1123@uestc.edu.cn.
المصدر: Cell death & disease [Cell Death Dis] 2024 Aug 15; Vol. 15 (8), pp. 594. Date of Electronic Publication: 2024 Aug 15.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101524092 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-4889 (Electronic) NLM ISO Abbreviation: Cell Death Dis Subsets: MEDLINE
أسماء مطبوعة: Original Publication: London : Nature Pub. Group
مواضيع طبية MeSH: Calcium*/metabolism , Cerebellar Ataxia*/metabolism , Cerebellar Ataxia*/pathology , Cerebellar Ataxia*/genetics , Large-Conductance Calcium-Activated Potassium Channels*/metabolism , Large-Conductance Calcium-Activated Potassium Channels*/genetics , Purkinje Cells*/metabolism , Purkinje Cells*/pathology , Toll-Like Receptor 4*/metabolism, Animals ; Mice ; Cytosol/metabolism ; Homeostasis ; Mice, Inbred C57BL ; Mice, Knockout ; Mitochondria/metabolism
مستخلص: Toll-like receptor (TLR) 4 contributes to be the induction of neuroinflammation by recognizing pathology-associated ligands and activating microglia. In addition, numerous physiological signaling factors act as agonists or antagonists of TLR4 expressed by non-immune cells. Recently, TLR4 was found to be highly expressed in cerebellar Purkinje neurons (PNs) and involved in the maintenance of motor coordination through non-immune pathways, but the precise mechanisms remain unclear. Here we report that mice with PN specific TLR4 deletion (TLR4 PKO mice) exhibited motor impairments consistent with cerebellar ataxia, reduced PN dendritic arborization and spine density, fewer parallel fiber (PF) - PN and climbing fiber (CF) - PN synapses, reduced BK channel expression, and impaired BK-mediated after-hyperpolarization, collectively leading to abnormal PN firing. Moreover, the impaired PN firing in TLR4 PKO mice could be rescued with BK channel opener. The PNs of TLR4 PKO mice also exhibited abnormal mitochondrial structure, disrupted mitochondrial endoplasmic reticulum tethering, and reduced cytosolic calcium, changes that may underly abnormal PN firing and ultimately drive ataxia. These results identify a previously unknown role for TLR4 in regulating PN firing and maintaining cerebellar function.
(© 2024. The Author(s).)
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معلومات مُعتمدة: 82171355 National Natural Science Foundation of China (National Science Foundation of China); 82001216 National Natural Science Foundation of China (National Science Foundation of China); 2021M700699 China Postdoctoral Science Foundation; 2024NSFSC0614 Department of Science and Technology of Sichuan Province (Sichuan Provincial Department of Science and Technology)
المشرفين على المادة: SY7Q814VUP (Calcium)
0 (Large-Conductance Calcium-Activated Potassium Channels)
0 (Tlr4 protein, mouse)
0 (Toll-Like Receptor 4)
تواريخ الأحداث: Date Created: 20240815 Date Completed: 20240815 Latest Revision: 20240822
رمز التحديث: 20240822
مُعرف محوري في PubMed: PMC11327311
DOI: 10.1038/s41419-024-06988-w
PMID: 39147737
قاعدة البيانات: MEDLINE
الوصف
تدمد:2041-4889
DOI:10.1038/s41419-024-06988-w