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Granulovacuolar degeneration bodies are neuron-selective lysosomal structures induced by intracellular tau pathology

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العنوان: Granulovacuolar degeneration bodies are neuron-selective lysosomal structures induced by intracellular tau pathology
المؤلفون: Markus Tolnay, Wiep Scheper, Sonia Vazquez-Sanchez, Florence Clavaguera, René J. P. Musters, Jeroen J.M. Hoozemans, Anna Nölle, Matthijs Verhage, Anna Maria van Ziel, Ernesto Berenjeno-Correa, Anna Bonaterra-Pastra, Jan R.T. van Weering, Vera I. Wiersma
المساهمون: Vrije Universiteit Amsterdam [Amsterdam] (VU), Vrije Universiteit Medical Centre (VUMC), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University Hospital Basel [Basel], Academic Medical Center, Gestionnaire, Hal Sorbonne Université, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Functional Genomics, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Human genetics, Pathology, Physiology, AII - Inflammatory diseases
المصدر: Acta Neuropathologica
Acta Neuropathologica, Springer Verlag, 2019, 1 (6), pp.943-970. ⟨10.1007/s00401-019-02046-4⟩
Wiersma, V I, van Ziel, A M, Vazquez-Sanchez, S, Nölle, A, Berenjeno-Correa, E, Bonaterra-Pastra, A, Clavaguera, F, Tolnay, M, Musters, R J P, van Weering, J R T, Verhage, M, Hoozemans, J J M & Scheper, W 2019, ' Granulovacuolar degeneration bodies are neuron-selective lysosomal structures induced by intracellular tau pathology ', Acta Neuropathologica, vol. 138, no. 6, pp. 943-970 . https://doi.org/10.1007/s00401-019-02046-4
Acta neuropathologica, 138(6), 943-970. Springer Verlag
Acta Neuropathologica, 2019, 1 (6), pp.943-970. ⟨10.1007/s00401-019-02046-4⟩
Acta Neuropathologica, 138(6), 943-970. Springer Verlag
بيانات النشر: Springer Science and Business Media LLC, 2019.
سنة النشر: 2019
مصطلحات موضوعية: Male, 0301 basic medicine, Tau pathology, [SDV]Life Sciences [q-bio], Endocytic cycle, Granulovacuolar degeneration bodies, Mice, Transgenic, tau Proteins, Vacuole, Pathology and Forensic Medicine, Green fluorescent protein, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Lysosome, medicine, Animals, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Cells, Cultured, Aged, Aged, 80 and over, Neurons, Original Paper, LAMP1, Chemistry, Brain, Human brain, Casein kinase 1 δ, 3. Good health, Cell biology, Mice, Inbred C57BL, [SDV] Life Sciences [q-bio], Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, Tauopathies, Astrocytes, Vacuoles, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), Neuron, Lysosomes, 030217 neurology & neurosurgery, Intracellular, Drugs, Chinese Herbal
الوصف: Granulovacuolar degeneration bodies (GVBs) are membrane-bound vacuolar structures harboring a dense core that accumulate in the brains of patients with neurodegenerative disorders, including Alzheimer’s disease and other tauopathies. Insight into the origin of GVBs and their connection to tau pathology has been limited by the lack of suitable experimental models for GVB formation. Here, we used confocal, automated, super-resolution and electron microscopy to demonstrate that the seeding of tau pathology triggers the formation of GVBs in different mouse models in vivo and in primary mouse neurons in vitro. Seeding-induced intracellular tau aggregation, but not seed exposure alone, causes GVB formation in cultured neurons, but not in astrocytes. The extent of tau pathology strongly correlates with the GVB load. Tau-induced GVBs are immunoreactive for the established GVB markers CK1δ, CK1ɛ, CHMP2B, pPERK, peIF2α and pIRE1α and contain a LAMP1- and LIMP2-positive single membrane that surrounds the dense core and vacuole. The proteolysis reporter DQ-BSA is detected in the majority of GVBs, demonstrating that GVBs contain degraded endocytic cargo. GFP-tagged CK1δ accumulates in the GVB core, whereas GFP-tagged tau or GFP alone does not, indicating selective targeting of cytosolic proteins to GVBs. Taken together, we established the first in vitro model for GVB formation by seeding tau pathology in primary neurons. The tau-induced GVBs have the marker signature and morphological characteristics of GVBs in the human brain. We show that GVBs are lysosomal structures distinguished by the accumulation of a characteristic subset of proteins in a dense core. Electronic supplementary material The online version of this article (10.1007/s00401-019-02046-4) contains supplementary material, which is available to authorized users.
وصف الملف: application/pdf
تدمد: 1432-0533
0001-6322
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f7b042e34c450b7a0bb291d6de0570e8
https://doi.org/10.1007/s00401-019-02046-4
حقوق: OPEN
رقم الأكسشن: edsair.doi.dedup.....f7b042e34c450b7a0bb291d6de0570e8
قاعدة البيانات: OpenAIRE
الوصف
تدمد:14320533
00016322