Phosphatidylinositol‐4,5‐bisphosphate is enriched in granulovacuolar degeneration bodies and neurofibrillary tangles

Nishikawa, Tomokazu; Takahashi, Tetsuya; Nakamori, Masahiro; Yamazaki, Yu; Kurashige, Takashi; Nagano, Yoshito; Nishida, Yoshihiko; Izumi, Yuishin; Matsumoto, Masayasu

doi:10.1111/nan.12056

Cited by 23 publications

(16 citation statements)

References 33 publications

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“…Various patterns of PtdIns(4,5)P2 immunoreactivity are found in pyramidal neurons of individuals with AD and other neurodegenerative diseases Some PtdIns(4,5)P2-immunopositive materials exhibited 3-to 5-lm-diameter vesicular structures with central granules that were surrounded by a halo-like clear zone and an outer membrane, characteristics that are indicative of GVD bodies. CK-1d, a marker of GVD bodies [9,13], was colocalized with PtdIns(4,5)P2, suggesting that PtdIns(4,5)P2 is a constituent of GVD bodies, as previously reported ( Figure 1A) [4]. The other PtdIns(4,5)P2-immunopositive materials exhibited granules that were clustered and piled up like NFTs.…”

Section: Resultssupporting

confidence: 82%

“…We previously reported that charged multivesicular body protein 2B (CHMP2B), an endosome-related protein, and cyclin-dependent kinase 5 (CDK5), a tau kinase, are present in GVD bodies [2,3]. We have also revealed that phosphatidylinositol-4,5bisphosphate [PtdIns(4,5)P2], a phospholipid associated with lipid rafts, exhibits identical immunoreactivity in GVD bodies and NFTs [4]. In addition, double immunofluorescence staining revealed that PtdIns(4,5) P2-immunopositive granules within NFTs were not colocalized with phosphorylated tau.…”

Section: Introductionmentioning

confidence: 99%

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The identification of raft‐derived tau‐associated vesicles that are incorporated into immature tangles and paired helical filaments

Nishikawa

Nakamori

Hosomi

et al. 2015

Neuropathology Appl Neurobio

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, have also been revealed as constituents of NFTs. Flotillin-1 and PtdIns(4,5)P2 are considered markers of raft microdomains, whereas CDK5 is a tau kinase. Therefore, we hypothesized that NFTs have a relationship with raft domains and the tau phosphorylation that occurs within NFTs. Methods: We investigated six cases of AD, six cases of other neurodegenerative diseases with NFTs and three control cases. We analysed the PtdIns(4,5)P2-immunopositive material in detail, using super-resolution microscopy and electron microscopy to elucidate its pattern of expression. We also investigated the spatial relationship between the PtdIns(4,5)P2-immunopositive material and tau kinases through double immunofluorescence analysis. Results: Pretangles contained either paired helical filaments (PHFs) or PtdIns(4,5)P2-immunopositive small vesicles (approximately 1 lm in diameter) with nearly identical topology to granulovacuolar degeneration (GVD) bodies. Various combinations of these vesicles and GVD bodies, the latter of which are pathological hallmarks observed within the neurons of AD patients, were found concurrently in neurons. These vesicles and GVD bodies were both immunopositive not only for PtdIns(4,5)P2, but also for several tau kinases such as glycogen synthase kinase-3b and spleen tyrosine kinase. Conclusions: These observations suggest that clusters of raft-derived vesicles that resemble GVD bodies are substructures of pretangles other than PHFs. These tau kinase-bearing vesicles are likely involved in the modification of tau protein and in NFT formation.

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Section: Resultssupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

The identification of raft‐derived tau‐associated vesicles that are incorporated into immature tangles and paired helical filaments

Nishikawa

Nakamori

Hosomi

et al. 2015

Neuropathology Appl Neurobio

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“…The estimated isoelectric point (pI) of PICALM whole protein (isoform 1 with 652 amino acids) is 7.70 (Goedert et al, 1996). Interestingly, it has been reported that PIP 2 (4,5) is enriched in NFTs and GVDs (Nishikawa et al, 2014). PICALM directly interacts with PIP 2 via its N-terminal ANTH domain (Ford et al, 2001), and PICALM association to NFTs might be driven by this interaction.…”

Section: Discussionmentioning

confidence: 99%

Level of PICALM, a key component of clathrin-mediated endocytosis, is correlated with levels of phosphotau and autophagy-related proteins and is associated with tau inclusions in AD, PSP and Pick disease

Ando

Tomimura

Sazdovitch

et al. 2016

Neurobiology of Disease

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Single nucleotide polymorphisms in PICALM, a key component of clathrin-mediated endocytosis machinery, have been identified as genetic susceptibility loci for late onset Alzheimer's disease (LOAD). We previously reported that PICALM protein levels were decreased in AD brains and that PICALM was co-localised with neurofibrillary tangles in LOAD, familial AD with PSEN1 mutations and Down syndrome. In the present study, we analysed PICALM expression, cell localisation and association with pathological cellular inclusions in other tauopathies and in non-tau related neurodegenerative diseases. We observed that PICALM was associated with neuronal tau pathology in Pick disease and in progressive supranuclear palsy (PSP) and co-localised with both 3R and 4R tau positive inclusions unlike in corticobasal degeneration (CBD) or in frontotemporal lobar degeneration (FTLD)-MAPT P301L. PICALM immunoreactivities were not detected in tau-positive tufted astrocytes in PSP, astrocytic plaques in CBD, Lewy bodies in Lewy body disease, diffuse type (LBD) and in TDP-43-positive inclusions in FTLD. In the frontal cortex in tauopathies, the ratio of insoluble to soluble PICALM was increased while the level of soluble PICALM was decreased and was inversely correlated with the level of phosphotau. PICALM decrease was also significantly correlated with increased LC3-II and decreased Beclin-1 levels in tauopathies and in non-tau related neurodegenerative diseases. These results suggest that there is a close relationship between abnormal PICALM processing, tau pathology and impairment of autophagy in human neurodegenerative diseases.

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“…Following its local generation, PI(4,5)P 2 activates the ezrin/radixin/moesin proteins required for uropod retraction [30,31]. A co-localization of PI(4,5)P 2 and flotillins was also observed in pathological neuronal structures typical for the brains of Alzheimer's disease patients, suggesting their common involvement in neurodegeneration [136]. Flotillins have also been indicated as regulators of the PI3-kinase/AKT pathway crucial for cancer cell survival [137,138].…”

Section: Flotillins Affect Sphingosine-1-phosphate Signaling and Are mentioning

confidence: 95%

Flotillins: At the Intersection of Protein S-Palmitoylation and Lipid-Mediated Signaling

Kwiatkowska

Matveichuk

Fronk

et al. 2020

IJMS

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Flotillin-1 and flotillin-2 are ubiquitously expressed, membrane-associated proteins involved in multifarious cellular events from cell signaling, endocytosis, and protein trafficking to gene expression. They also contribute to oncogenic signaling. Flotillins bind the cytosolic leaflet of the plasma membrane and endomembranes and, upon hetero-oligomerization, serve as scaffolds facilitating the assembly of multiprotein complexes at the membrane–cytosol interface. Additional functions unique to flotillin-1 have been discovered recently. The membrane-binding of flotillins is regulated by S-palmitoylation and N-myristoylation, hydrophobic interactions involving specific regions of the polypeptide chain and, to some extent, also by their oligomerization. All these factors endow flotillins with an ability to associate with the sphingolipid/cholesterol-rich plasma membrane domains called rafts. In this review, we focus on the critical input of lipids to the regulation of the flotillin association with rafts and thereby to their functioning. In particular, we discuss how the recent developments in the field of protein S-palmitoylation have contributed to the understanding of flotillin1/2-mediated processes, including endocytosis, and of those dependent exclusively on flotillin-1. We also emphasize that flotillins affect directly or indirectly the cellular levels of lipids involved in diverse signaling cascades, including sphingosine-1-phosphate and PI(4,5)P2. The mutual relations between flotillins and distinct lipids are key to the regulation of their involvement in numerous cellular processes.

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Phosphatidylinositol‐4,5‐bisphosphate is enriched in granulovacuolar degeneration bodies and neurofibrillary tangles

Cited by 23 publications

References 33 publications

The identification of raft‐derived tau‐associated vesicles that are incorporated into immature tangles and paired helical filaments

The identification of raft‐derived tau‐associated vesicles that are incorporated into immature tangles and paired helical filaments

Level of PICALM, a key component of clathrin-mediated endocytosis, is correlated with levels of phosphotau and autophagy-related proteins and is associated with tau inclusions in AD, PSP and Pick disease

Flotillins: At the Intersection of Protein S-Palmitoylation and Lipid-Mediated Signaling

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