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

Abstract

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 materialThe online version of this article (10.1007/s00401-019-02046-4) contains supplementary material, which is available to authorized users.

Aggregates of RNA Binding Proteins and ER Chaperones Linked to Exosomes in Granulovacuolar Degeneration of the Alzheimer’s Disease Brain

“…trigger the formation of GVBs [5,7,25]. Other recent studies have demonstrated that DPR aggregates contribute to GVD in neurons of ALS/FTD patients with C9orf72 expansion [15].…”

“…pTau can alter autophagy at multiple steps [48] and can trigger the formation of GVBs in vivo as well as in vitro [25]. Similarly, DPR aggregates, which alter autophagy pathways [26], were found within GVBs in neurons of ALS/FTD patients with C9orf72 expansion [15].…”

“…Searching for factors that trigger GVD, Wiersma et al recently found that seeding of tau pathology initiates the formation of GVBs in tau P301 L and tau P301 S tg mice in vivo and in primary mouse neurons in vitro [25]. Furthermore, dipeptide repeat (DPR) aggregates, which are mainly processed via autophagy pathway [26] were found within GVBs in neurons of ALS/frontotemporal dementia (FTD) patients with C9orf72 expansion [15].…”

Untangling the origin and function of granulovacuolar degeneration bodies in neurodegenerative proteinopathies

“…In 1980, a review on senile dementia stated: "In the absence of an experimental model for the induction of granulovacuolar change, this characteristic cytological change has been largely ignored, and at the present time no hypothesis for induction is available" [11]. It took 4 more decades to the publication of the first experimental model for GVB formation in vitro, in which GVBs are induced by the seeding of intracellular tau pathology [143]. This opens new avenues for future research into the mechanism and function of GVB formation.…”

Granulovacuolar degeneration bodies: red alert for neurons with MAPT/tau pathology

“…In our recent publication [1], we present novel experimental models for GVB formation in mouse brain and cultured primary mouse neurons. GVBs form after the introduction of intracellular MAPT pathology using exposure to human brain-derived or recombinant MAPT aggregates.…”