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

ABSTRACT: In the brains of tauopathy patients, tau pathology coincides with the presence of granulovacuolar degeneration bodies (GVBs) both at the regional and cellular level. Recently, it was shown that intracellular tau pathology causes GVB formation in experimental models thus explaining the strong correlation between these neuropathological hallmarks in the human brain. These novel models of GVB formation provide opportunities for future research into GVB biology, but also urge reevaluation of previous post-mortem observations. Here, we review neuropathological data on GVBs in tauopathies and other neurodegenerative proteinopathies. We discuss the possibility that intracellular aggregates composed of proteins other than tau are also able to induce GVB formation. Furthermore, the potential mechanisms of GVB formation and the downstream functional implications hereof are outlined in view of the current available data. In addition, we provide guidelines for the identification of GVBs in tissue and cell models that will help to facilitate and streamline research towards the elucidation of the role of these enigmatic and understudied structures in neurodegeneration.

SUBMITTER: Wiersma VI

PROVIDER: S-EPMC7469111 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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

Wiersma Vera I VI Hoozemans Jeroen J M JJM Scheper Wiep W

Acta neuropathologica communications 20200903 1

In the brains of tauopathy patients, tau pathology coincides with the presence of granulovacuolar degeneration bodies (GVBs) both at the regional and cellular level. Recently, it was shown that intracellular tau pathology causes GVB formation in experimental models thus explaining the strong correlation between these neuropathological hallmarks in the human brain. These novel models of GVB formation provide opportunities for future research into GVB biology, but also urge reevaluation of previou ...[more]

PMID: 32883341

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Project description:BackgroundGranulovacuolar degeneration bodies (GVBs) are intracellular vesicular structures that commonly accompany pathological tau accumulations in neurons of patients with tauopathies. Recently, we developed the first model for GVBs in primary neurons, that requires exogenous tau seeds to elicit tau aggregation. This model allowed the identification of GVBs as proteolytically active lysosomes induced by tau pathology. GVBs selectively accumulate cargo in a dense core, that shows differential and inconsistent immunopositivity for (phosphorylated) tau epitopes. Despite the strong evidence connecting GVBs to tau pathology, these structures have been reported in neurons without apparent pathology in brain tissue of tauopathy patients. Additionally, GVBs and putative GVBs have also been reported in the brain of patients with non-tau proteinopathies. Here, we investigated the connection between pathological protein assemblies and GVBs in more detail.MethodsThis study combined newly developed primary neuron models for tau and α-synuclein pathology with observations in human brain tissue from tauopathy and Parkinson's disease patients. Immunolabeling and imaging techniques were employed for extensive characterisation of pathological proteins and GVBs. Quantitative data were obtained by high-content automated microscopy as well as single-cell analysis of confocal images.ResultsEmploying a novel seed-independent neuronal tau/GVB model, we show that in the context of tauopathy, GVBs are inseparably associated with the presence of cytosolic pathological tau and that intracellular tau aggregation precedes GVB formation, strengthening the causal relationship between pathological accumulation of tau and GVBs. We also report that GVBs are inseparably associated with pathological tau at the single-cell level in the hippocampus of tauopathy patients. Paradoxically, we demonstrate the presence of GVBs in the substantia nigra of Parkinson's disease patients and in a primary neuron model for α-synuclein pathology. GVBs in this newly developed α-synuclein/GVB model are induced in the absence of cytosolic pathological tau accumulations. GVBs in the context of tau or α-synuclein pathology showed similar immunoreactivity for different phosphorylated tau epitopes. The phosphorylated tau immunoreactivity signature of GVBs is therefore independent of the presence of cytosolic tau pathology.ConclusionOur data identify the emergence of GVBs as a more generalised response to cytosolic protein pathology.

Project description:Neurodegenerative proteinopathies are characterized by progressive cell loss that is preceded by the mislocalization and aberrant accumulation of proteins prone to aggregation. Despite their different physiological functions, disease-related proteins like tau, α-synuclein, TAR DNA binding protein-43, fused in sarcoma and mutant huntingtin, all share low complexity regions that can mediate their liquid-liquid phase transitions. The proteins' phase transitions can range from native monomers to soluble oligomers, liquid droplets and further to irreversible, often-mislocalized aggregates that characterize the stages and severity of neurodegenerative diseases. Recent advances into the underlying pathogenic mechanisms have associated mislocalization and aberrant accumulation of disease-related proteins with defective nucleocytoplasmic transport and its mediators called karyopherins. These studies identify karyopherin abnormalities in amyotrophic lateral sclerosis, frontotemporal dementia, Alzheimer's disease, and synucleinopathies including Parkinson's disease and dementia with Lewy bodies, that range from altered expression levels to the subcellular mislocalization and aggregation of karyopherin α and β proteins. The reported findings reveal that in addition to their classical function in nuclear import and export, karyopherins can also act as chaperones by shielding aggregation-prone proteins against misfolding, accumulation and irreversible phase-transition into insoluble aggregates. Karyopherin abnormalities can, therefore, be both the cause and consequence of protein mislocalization and aggregate formation in degenerative proteinopathies. The resulting vicious feedback cycle of karyopherin pathology and proteinopathy identifies karyopherin abnormalities as a common denominator of onset and progression of neurodegenerative disease. Pharmacological targeting of karyopherins, already in clinical trials as therapeutic intervention targeting cancers such as glioblastoma and viral infections like COVID-19, may therefore represent a promising new avenue for disease-modifying treatments in neurodegenerative proteinopathies.

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

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

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