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Microglial NFκB-TNFα hyperactivation induces obsessive-compulsive behavior in mouse models of progranulin-deficient frontotemporal dementia.
Krabbe, Grietje; Minami, S Sakura; Etchegaray, Jon I; Taneja, Praveen; Djukic, Biljana; Davalos, Dimitrios; Le, David; Lo, Iris; Zhan, Lihong; Reichert, Meredith C; Sayed, Faten; Merlini, Mario; Ward, Michael E; Perry, David C; Lee, Suzee E; Sias, Ana; Parkhurst, Christopher N; Gan, Wen-Biao; Akassoglou, Katerina; Miller, Bruce L; Farese, Robert V; Gan, Li.
Afiliación
  • Krabbe G; Gladstone Institute of Neurological Diseases, University of California, San Francisco, CA 94158.
  • Minami SS; Department of Neurology, University of California, San Francisco, CA 94158.
  • Etchegaray JI; Gladstone Institute of Neurological Diseases, University of California, San Francisco, CA 94158.
  • Taneja P; Department of Neurology, University of California, San Francisco, CA 94158.
  • Djukic B; Gladstone Institute of Neurological Diseases, University of California, San Francisco, CA 94158.
  • Davalos D; Department of Neurology, University of California, San Francisco, CA 94158.
  • Le D; Gladstone Institute of Neurological Diseases, University of California, San Francisco, CA 94158.
  • Lo I; Gladstone Institute of Neurological Diseases, University of California, San Francisco, CA 94158.
  • Zhan L; Gladstone Institute of Neurological Diseases, University of California, San Francisco, CA 94158.
  • Reichert MC; Gladstone Institute of Neurological Diseases, University of California, San Francisco, CA 94158.
  • Sayed F; Gladstone Institute of Neurological Diseases, University of California, San Francisco, CA 94158.
  • Merlini M; Gladstone Institute of Neurological Diseases, University of California, San Francisco, CA 94158.
  • Ward ME; Department of Neurology, University of California, San Francisco, CA 94158.
  • Perry DC; Gladstone Institute of Neurological Diseases, University of California, San Francisco, CA 94158.
  • Lee SE; Department of Neurology, University of California, San Francisco, CA 94158.
  • Sias A; Neuroscience Graduate Program, University of California, San Francisco, CA 94158.
  • Parkhurst CN; Gladstone Institute of Neurological Diseases, University of California, San Francisco, CA 94158.
  • Gan WB; Gladstone Institute of Neurological Diseases, University of California, San Francisco, CA 94158.
  • Akassoglou K; Department of Neurology, University of California, San Francisco, CA 94158.
  • Miller BL; Department of Neurology, University of California, San Francisco, CA 94158.
  • Farese RV; Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA 94158.
  • Gan L; Department of Neurology, University of California, San Francisco, CA 94158.
Proc Natl Acad Sci U S A ; 114(19): 5029-5034, 2017 05 09.
Article en En | MEDLINE | ID: mdl-28438992
Frontotemporal dementia (FTD) is the second most common dementia before 65 years of age. Haploinsufficiency in the progranulin (GRN) gene accounts for 10% of all cases of familial FTD. GRN mutation carriers have an increased risk of autoimmune disorders, accompanied by elevated levels of tissue necrosis factor (TNF) α. We examined behavioral alterations related to obsessive-compulsive disorder (OCD) and the role of TNFα and related signaling pathways in FTD patients with GRN mutations and in mice lacking progranulin (PGRN). We found that patients and mice with GRN mutations displayed OCD and self-grooming (an OCD-like behavior in mice), respectively. Furthermore, medium spiny neurons in the nucleus accumbens, an area implicated in development of OCD, display hyperexcitability in PGRN knockout mice. Reducing levels of TNFα in PGRN knockout mice abolished excessive self-grooming and the associated hyperexcitability of medium spiny neurons of the nucleus accumbens. In the brain, PGRN is highly expressed in microglia, which are a major source of TNFα. We therefore deleted PGRN specifically in microglia and found that it was sufficient to induce excessive grooming. Importantly, excessive grooming in these mice was prevented by inactivating nuclear factor κB (NF-κB) in microglia/myeloid cells. Our findings suggest that PGRN deficiency leads to excessive NF-κB activation in microglia and elevated TNFα signaling, which in turn lead to hyperexcitability of medium spiny neurons and OCD-like behavior.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: FN-kappa B / Factor de Necrosis Tumoral alfa / Microglía / Péptidos y Proteínas de Señalización Intercelular / Demencia Frontotemporal / Trastorno Obsesivo Compulsivo Tipo de estudio: Prognostic_studies Límite: Aged / Aged80 / Animals / Female / Humans / Male Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2017 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: FN-kappa B / Factor de Necrosis Tumoral alfa / Microglía / Péptidos y Proteínas de Señalización Intercelular / Demencia Frontotemporal / Trastorno Obsesivo Compulsivo Tipo de estudio: Prognostic_studies Límite: Aged / Aged80 / Animals / Female / Humans / Male Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2017 Tipo del documento: Article Pais de publicación: Estados Unidos