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.

Cellular localization of p-tau217 in brain and its association with p-tau217 plasma levels

“…These structures are defined as large membrane-bound vacuoles containing aggregated proteins including p-tau [29], TDP-43 [21], and Aβ [14]. The GVBs are commonly seen in patients with tauopathies and are highly correlated with the spreading of tau pathology, in a stereotypical pattern from the entorhinal cortex to the neocortex, hypothalamus, amygdala, and eventually frontal and parietal cortex [21,26]. Although found throughout the brain, GVBs are most frequently seen in CA1 neurons of AD patients [26].…”

“…The GVBs are commonly seen in patients with tauopathies and are highly correlated with the spreading of tau pathology, in a stereotypical pattern from the entorhinal cortex to the neocortex, hypothalamus, amygdala, and eventually frontal and parietal cortex [21,26]. Although found throughout the brain, GVBs are most frequently seen in CA1 neurons of AD patients [26]. In line with these observations, the Ckid + / p-tau217 + found in our study was most prominent in the CA1 region, but also detected in the EC, albeit in general with a smaller number of vesicles in each cell.…”

The proteome of granulovacuolar degeneration and neurofibrillary tangles in Alzheimer’s disease

“…During this process of cellular stress, GVD is initiated. While the increase of intracellular pTau levels might elicit GVD formation, it is still elusive whether GVD is a protective or degenerative response [ 72 ].…”

Tau aggregation and its relation to selected forms of neuronal cell death

“…Phospho-tau has been reported to be contained within GvB, alongside an unusually large cohort of other phosphoproteins and kinases such as CK1∂ [ 43 ]. GvB vacuoles were suggested to be late-stage autophagic organelles [ 44 ] and recently GvBs have been identified as specific neuronal lysosomes that form as a direct result of tau aggregation (induced by seeding) due to impaired vesicle trafficking [ 45 ]. Since tau fibril formation is dependent on tau concentration, sequestering tau in vesicles might contribute to increased tau toxicity or reduce it, as hypothesised in [ 46 ].…”