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Microglia contribute to polyG-dependent neurodegeneration in neuronal intranuclear inclusion disease.
Zhong, Shaoping; Lian, Yangye; Zhou, Binbin; Ren, Ruiqing; Duan, Lewei; Pan, Yuyin; Gong, Yuchen; Wu, Xiaoling; Cheng, Dengfeng; Zhang, Puming; Lu, Boxun; Wang, Xin; Ding, Jing.
Afiliación
  • Zhong S; Department of Neurology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China.
  • Lian Y; Department of Neurology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China.
  • Zhou B; Department of Neurology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China.
  • Ren R; Department of Neurology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China.
  • Duan L; Shanghai Medical College, Fudan University, Shanghai, China.
  • Pan Y; Department of Neurology at Huashan Hospital, State Key Laboratory of Medical Neurobiology, School of Life Sciences, Fudan University, Shanghai, China.
  • Gong Y; School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.
  • Wu X; Department of Neurology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China.
  • Cheng D; Department of Nuclear Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
  • Zhang P; School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.
  • Lu B; Department of Neurology at Huashan Hospital, State Key Laboratory of Medical Neurobiology, School of Life Sciences, Fudan University, Shanghai, China.
  • Wang X; Department of Neurology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China.
  • Ding J; The State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, China.
Acta Neuropathol ; 148(1): 21, 2024 Aug 16.
Article en En | MEDLINE | ID: mdl-39150562
ABSTRACT
Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder caused by the expansion of GGC trinucleotide repeats in NOTCH2NLC gene. Despite identifying uN2CpolyG, a toxic polyglycine (polyG) protein translated by expanded GGC repeats, the exact pathogenic mechanisms of NIID remain unclear. In this study, we investigated the role of polyG by expressing various forms of NOTCH2NLC in mice the wild-type, the expanded form with 100 GGC repeats (either translating or not translating into uN2CpolyG), and the mutated form that encodes a pure polyG without GGC-repeat RNA and the C-terminal stretch (uN2CpolyG-dCT). Both uN2CpolyG and uN2CpolyG-dCT induced the formation of inclusions composed by filamentous materials and resulted in neurodegenerative phenotypes in mice, including impaired motor and cognitive performance, shortened lifespan, and pathologic lesions such as white-matter lesions, microgliosis, and astrogliosis. In contrast, expressing GGC-repeat RNA alone was non-pathogenic. Through bulk and single-nuclei RNA sequencing, we identified common molecular signatures linked to the expression of uN2CpolyG and uN2CpolyG-dCT, particularly the upregulation of inflammation and microglia markers, and the downregulation of immediate early genes and splicing factors. Importantly, microglia-mediated inflammation was visualized in NIID patients using positron emission tomography, correlating with levels of white-matter atrophy. Furthermore, microglia ablation ameliorated neurodegenerative phenotypes and transcriptional alterations in uN2CpolyG-expressing mice but did not affect polyG inclusions. Together, these results demonstrate that polyG is crucial for the pathogenesis of NIID and highlight the significant role of microglia in polyG-induced neurodegeneration.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Microglía / Enfermedades Neurodegenerativas / Cuerpos de Inclusión Intranucleares Límite: Animals / Female / Humans / Male Idioma: En Revista: Acta Neuropathol Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Alemania
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Microglía / Enfermedades Neurodegenerativas / Cuerpos de Inclusión Intranucleares Límite: Animals / Female / Humans / Male Idioma: En Revista: Acta Neuropathol Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Alemania