Untangling the origin and function of granulovacuolar degeneration bodies in neurodegenerative proteinopathies
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(2020) 8:153
REVIEW
Open Access
Untangling the origin and function of granulovacuolar degeneration bodies in neurodegenerative proteinopathies Vera I. Wiersma1,2, Jeroen J. M. Hoozemans3 and Wiep Scheper1,2*
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. Keywords: Granulovacuolar degeneration bodies, Tau pathology, Neurodegenerative proteinopathies, Lysosomes Neurodegenerative tauopathies, including Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD) share a common neuropathological feature: the deposition of misfolded and hyperphosphorylated tau protein in multimeric, highly-ordered, filamentous aggregates in the central nervous system. The existence of familial forms of FTLD that are caused by mutations in the tau-encoding MAPT gene underscores the key role of tau in disease pathogenesis [49, 109, 121]. Indeed, also in sporadic tauopathy patients the accumulation of aggregated tau strongly correlates with neuronal loss and clinical symptoms, as demonstrated by neuropathological studies [4, 34, 51, 98] * Correspondence: [email protected] 1 Department of Clinical Genetics, Amsterdam University Medical Centers location VUmc, Amsterdam, The Netherlands 2 Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit (VU), De Boelelaan 1085, 1081 HV Amsterdam, The Netherlands Full list of author information is available at the end of the article
and more recently in living patients by tau positron emission tomography [77]. Despite this strong association between tau aggregation and neurodegeneration, the mechanisms that connect the two are largely unknown. Here, we focus on an intracellular alteration that coincides with the formation of tau aggregates: the emergence of granulovacuolar degeneration bodies (GVBs). GVBs were first observed in 1911 by Simchowicz, in pyramidal neurons in the hippocampus of AD patients [120]. GVBs are memb
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