Increased prevalence of granulovacuolar degeneration in C9orf72 mutation

Riku, Yuichi; Duyckaerts, Charles; Boluda, Susana; Plu, Isabelle; Ber, Isabelle Le; Millecamps, Stéphanie; Salachas, François; Yoshida, Mari; Ando, Takashi; Katsuno, Masahisa; Sobue, Gen; Seilhean, Danielle

doi:10.1007/s00401-019-02028-6

Cited by 20 publications

(34 citation statements)

References 39 publications

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“…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]. Consistent with this we recently reported GVD pathology in cases of C9orf72-related FTLD [62].…”

Section: Discussionsupporting

confidence: 90%

“…Taken together, abnormal cytoplasmic RBP aggregates colocalize with GVBs, suggesting that RBP aggregates possibly trigger GVB formation and that GVBs might actually be involved in the removal of such aggregates. They are in line with a recent study showing that DPR aggregates contribute to GVD pathology in C9orf72-related FTLD/ALS [15].…”

Section: Rna Binding Protein Homeostasis and Gvbssupporting

confidence: 93%

“…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]. RBPs such as TDP-43 form aggregates in AD patient neurons and quite often granular pTDP-43 aggregates co-localize with GVBs in AD patient hippocampal neurons [29].…”

Section: Rna Binding Protein Homeostasis and Gvbsmentioning

confidence: 98%

“…GVBs were originally observed in hippocampal pyramidal neurons of senile dementia patients [11] and have subsequently been described in further neurodegenerative disorders [12] including tauopathies such as Guam disease [13], Pick's disease, and progressive supranuclear palsy as well as in the synucleinopathies, sporadic Parkinson's disease and dementia with Lewy bodies [14]. GVD has recently been reported in C9orf72 mediated familial amyotrophic lateral sclerosis (ALS) [15]. GVD can also be found at low frequency in brains of nonneurologically impaired aged persons [3,16].…”

Section: Introductionmentioning

confidence: 99%

“…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]. Similarly, recent studies have emphasized a functional interplay between ER function, autophagy, and RNA binding protein (RBP) homeostasis [27].…”

Section: Introductionmentioning

confidence: 99%

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

Yamoah

Tripathi

Sechi

et al. 2020

JAD

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Granulovacuolar degeneration (GVD) occurs in Alzheimer's disease (AD) brain due to compromised autophagy. Endoplasmic reticulum (ER) function and RNA binding protein (RBP) homeostasis regulate autophagy. We observed that the ER chaperones Glucose -regulated protein, 78 KDa (GRP78/BiP), Sigma receptor 1 (SigR1), and Vesicle-associated membrane protein associated protein B (VAPB) were elevated in many AD patients' subicular neurons. However, those neurons which were affected by GVD showed lower chaperone levels, and there was only minor co-localization of chaperones with GVD bodies (GVBs), suggesting that neurons lacking sufficient chaperone-mediated proteostasis enter the GVD pathway. Consistent with this notion, granular, incipient pTau aggregates in human AD and pR5 tau transgenic mouse neurons were regularly co-localized with increased chaperone immunoreactivity, whereas neurons with mature neurofibrillary tangles lacked both the chaperone buildup and significant GVD. On the other hand, APP/PS1 (APPswe/PSEN1dE9) transgenic mouse hippocampal neurons that are devoid of pTau accumulation displayed only few GVBs-like vesicles, which were still accompanied by prominent chaperone buildup. Identifying a potential trigger for GVD, we found cytoplasmic accumulations of RBPs including Matrin 3 and FUS as well as stress granules in GVBs of AD patient and pR5 mouse neurons. Interestingly, we observed that GVBs containing aggregated pTau and pTDP-43 were consistently co-localized with the exosomal marker Flotillin 1 in both AD and pR5 mice. In contrast, intraneuronal 82E1-immunoreactive amyloid-␤ in human AD and APP/PS1 mice only rarely co-localized with Flotillin 1-positive exosomal vesicles. We conclude that altered chaperone-mediated ER protein homeostasis and impaired autophagy manifesting in GVD are linked to both pTau and RBP accumulation and that some GVBs might be targeted to exocytosis.

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Section: Discussionsupporting

confidence: 90%

Section: Rna Binding Protein Homeostasis and Gvbssupporting

confidence: 93%

Section: Rna Binding Protein Homeostasis and Gvbsmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Yamoah

Tripathi

Sechi

et al. 2020

JAD

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Necrosome complex detected in granulovacuolar degeneration is associated with neuronal loss in Alzheimer’s disease

et al. 2019

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Alzheimer's disease (AD) is characterized by a specific pattern of neuropathological changes, including extracellular amyloid beta (Aβ) deposits, intracellular neurofibrillary tangles (NFTs), granulovacuolar degeneration (GVD) representing cytoplasmic vacuolar lesions, and synapse and neuronal loss. Necroptosis, a programmed form of necrosis, has recently been shown to be involved in AD. Necroptotic cell death is characterized by the assembly of the necrosome complex, consisting of phosphorylated proteins, i.e. receptor-interacting serine/threonineprotein kinase 1 and 3 (pRIPK1 and pRIPK3), and mixed lineage kinase domain-like protein (pMLKL). However, it is not yet clear whether necrosome assembly takes place in the brain regions showing AD-related neuronal loss, and whether it is associated with AD-related neuropathological changes. Here, we analyzed brains of AD, pathologically defined preclinical AD, and non-AD control cases to determine the neuropathological characteristics and distribution pattern of the necrosome components. We demonstrated that all three activated necrosome components can be detected in GVD lesions (GVDn+, i.e. GVD with activated necrosome) in neurons, and colocalized with classical GVD markers, such as pTDP-43 and CK1δ. GVDn+ neurons were inversely associated with the neuronal density in the early affected CA1 region of the hippocampus and in the late affected frontal cortex layer III. Finally, the distribution of non-phosphorylated proteins was studied. RIPK1 was mainly expressed in astrocytes and in GVD lesions, RIPK3 was detected in dystrophic neurites of neuritic plaques and in neurons. GVD lesions remained negative for non-phosphorylated RIPK3. MLKL could only be detected by western blotting showing an increase in p-preAD and AD cases. Accordingly, AD-related GVD lesions exhibited all components of the activated necrosome and were associated with reduced neuronal densities in the affected anatomical regions, and with AD-defining parameters, showing the strongest correlation and partial colocalization with NFT pathology. Therefore, we conclude that the presence of the necrosome in GVD plays a role in AD, possibly by representing an AD-specific form of necroptosis-related neuron death. Hence, necroptosis-related neuron loss could be an interesting therapeutic target for treating AD.

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

et al. 2021

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Granulovacuolar degeneration (GVD) is a common feature in Alzheimer’s disease (AD). The occurrence of GVD is closely associated with that of neurofibrillary tangles (NFTs) and GVD is even considered to be a pre-NFT stage in the disease process of AD. Currently, the composition of GVD bodies, the mechanisms associated with GVD and how GVD exactly relates to NFTs is not well understood. By combining immunohistochemistry (IHC) and laser microdissection (LMD) we isolated neurons with GVD and those bearing tangles separately from human post-mortem AD hippocampus (n = 12) using their typical markers casein kinase (CK)1δ and phosphorylated tau (AT8). Control neurons were isolated from cognitively healthy cases (n = 12). 3000 neurons per sample were used for proteome analysis by label free LC–MS/MS. In total 2596 proteins were quantified across samples and a significant change in abundance of 115 proteins in GVD and 197 in tangle bearing neurons was observed compared to control neurons. With IHC the presence of PPIA, TOMM34, HSP70, CHMP1A, TPPP and VXN was confirmed in GVD containing neurons. We found multiple proteins localizing specifically to the GVD bodies, with VXN and TOMM34 being the most prominent new protein markers for GVD bodies. In general, protein groups related to protein folding, proteasomal function, the endolysosomal pathway, microtubule and cytoskeletal related function, RNA processing and glycolysis were found to be changed in GVD neurons. In addition to these protein groups, tangle bearing neurons show a decrease in ribosomal proteins, as well as in various proteins related to protein folding. This study, for the first time, provides a comprehensive human based quantitative assessment of protein abundances in GVD and tangle bearing neurons. In line with previous functional data showing that tau pathology induces GVD, our data support the model that GVD is part of a pre-NFT stage representing a phase in which proteostasis and cellular homeostasis is disrupted. Elucidating the molecular mechanisms and cellular processes affected in GVD and its relation to the presence of tau pathology is highly relevant for the identification of new drug targets for therapy.

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Increased prevalence of granulovacuolar degeneration in C9orf72 mutation

Cited by 20 publications

References 39 publications

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

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

Necrosome complex detected in granulovacuolar degeneration is associated with neuronal loss in Alzheimer’s disease

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

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