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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.
Zhu, Jianwei; Qiu, Wenqiao; Wei, Fan; Zhang, Jin; Yuan, Ying; Liu, Ling; Cheng, Meixiong; Xiong, Huan; Xu, Ruxiang.
Afiliación
  • 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.
  • Zhang J; Department of Critical Care Medicine, Mianyang Orthopaedic Hospital, Mianyang, Sichuan Province, 621000, 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.
  • Xu R; 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.
Cell Death Dis ; 15(8): 594, 2024 Aug 15.
Article en En | MEDLINE | ID: mdl-39147737
ABSTRACT
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 (TLR4PKO 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 TLR4PKO mice could be rescued with BK channel opener. The PNs of TLR4PKO 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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Células de Purkinje / Ataxia Cerebelosa / Calcio / Canales de Potasio de Gran Conductancia Activados por el Calcio / Receptor Toll-Like 4 Límite: Animals Idioma: En Revista: Cell Death Dis Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Células de Purkinje / Ataxia Cerebelosa / Calcio / Canales de Potasio de Gran Conductancia Activados por el Calcio / Receptor Toll-Like 4 Límite: Animals Idioma: En Revista: Cell Death Dis Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido