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

  • Wiersma VI Center for Neurogenomics and Cognitive Research, Department of Functional Genomics, Faculty of Science, Vrije Universiteit (VU), De Boelelaan 1085, 1081 HV, Amsterdam, The Netherlands.
  • van Ziel AM Center for Neurogenomics and Cognitive Research, Department of Functional Genomics, Faculty of Science, Vrije Universiteit (VU), De Boelelaan 1085, 1081 HV, Amsterdam, The Netherlands.
  • Vazquez-Sanchez S Center for Neurogenomics and Cognitive Research, Department of Functional Genomics, Faculty of Science, Vrije Universiteit (VU), De Boelelaan 1085, 1081 HV, Amsterdam, The Netherlands.
  • Nölle A Department of Pathology, Amsterdam University Medical Centers Location VUmc, Amsterdam, The Netherlands.
  • Berenjeno-Correa E Center for Neurogenomics and Cognitive Research, Department of Functional Genomics, Faculty of Science, Vrije Universiteit (VU), De Boelelaan 1085, 1081 HV, Amsterdam, The Netherlands.
  • Bonaterra-Pastra A Center for Neurogenomics and Cognitive Research, Department of Functional Genomics, Faculty of Science, Vrije Universiteit (VU), De Boelelaan 1085, 1081 HV, Amsterdam, The Netherlands.
  • Clavaguera F Institut du Cerveau et de la Moelle épinière, INSERM U1127, CNRS UMR7225, Sorbonne Universités, Hôpital Pitié-Salpêtrière, Paris, France.
  • Tolnay M Institute of Medical Genetics and Pathology, University Hospital Basel, 4031, Basel, Switzerland.
  • Musters RJP Department of Physiology, Amsterdam University Medical Centers Location VUmc, Amsterdam, The Netherlands.
  • van Weering JRT Department of Clinical Genetics, Amsterdam University Medical Centers Location VUmc, Amsterdam, The Netherlands.
  • Verhage M Center for Neurogenomics and Cognitive Research, Department of Functional Genomics, Faculty of Science, Vrije Universiteit (VU), De Boelelaan 1085, 1081 HV, Amsterdam, The Netherlands.
  • Hoozemans JJM Department of Pathology, Amsterdam University Medical Centers Location VUmc, Amsterdam, The Netherlands.
  • Scheper W Center for Neurogenomics and Cognitive Research, Department of Functional Genomics, Faculty of Science, Vrije Universiteit (VU), De Boelelaan 1085, 1081 HV, Amsterdam, The Netherlands. w.scheper@amsterdamumc.nl.
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  • 2019-08-29
Published in:
  • Acta neuropathologica. - 2019
Casein kinase 1 δ
Granulovacuolar degeneration bodies
Lysosome
Tau pathology
Aged
Aged, 80 and over
Animals
Astrocytes
Brain
Cells, Cultured
Disease Models, Animal
Drugs, Chinese Herbal
Female
Humans
Lysosomes
Male
Mice, Inbred C57BL
Mice, Transgenic
Neurons
Tauopathies
Vacuoles
tau Proteins
English 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.
Language
  • English
Open access status
hybrid
Identifiers
Persistent URL
https://sonar.ch/global/documents/232669
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