TY - JOUR
T1 - Granulovacuolar degeneration bodies are neuron-selective lysosomal structures induced by intracellular tau pathology
AU - Wiersma, Vera I.
AU - van Ziel, Anna Maria
AU - Vazquez-Sanchez, Sonia
AU - Nölle, Anna
AU - Berenjeno-Correa, Ernesto
AU - Bonaterra-Pastra, Anna
AU - Clavaguera, Florence
AU - Tolnay, Markus
AU - Musters, René J. P.
AU - van Weering, Jan R. T.
AU - Verhage, Matthijs
AU - Hoozemans, Jeroen J. M.
AU - Scheper, Wiep
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
KW - Casein kinase 1 δ
KW - Granulovacuolar degeneration bodies
KW - Lysosome
KW - Tau pathology
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85071322554&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/31456031
UR - http://www.scopus.com/inward/record.url?scp=85071322554&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85071322554&partnerID=8YFLogxK
U2 - https://doi.org/10.1007/s00401-019-02046-4
DO - https://doi.org/10.1007/s00401-019-02046-4
M3 - Article
C2 - 31456031
SN - 0001-6322
VL - 138
SP - 943
EP - 970
JO - Acta Neuropathologica
JF - Acta Neuropathologica
IS - 6
ER -