Secretion of Tau via an Unconventional Non-vesicular Mechanism

Merezhko, Maria; Brunello, Cecilia A.; Xu, Yan; Vihinen, Helena; Jokitalo, Eija; Uronen, Riikka-Liisa; Huttunen, Henri J.

doi:10.1016/j.celrep.2018.10.078

Cited by 135 publications

(192 citation statements)

References 57 publications

(58 reference statements)

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“…Tau localizes to the PM in a clustered manner, and this localization is enhanced by overexpression or hyperphosphorylation, possibly as a consequence of increased levels of cytosolic tau or enhanced aggregation. Transmission electron microscopy revealed two types of tau clusters, with diameter ranging between 50 and 200 nm, at or very close to the PM [159]. Similar, reversible cation-sensitive clustering of tau has been previously reported for recombinant human tau in supported brain lipid membranes [161].…”

Section: Tau Secretion Directly Through the Plasma Membranesupporting

confidence: 82%

“…Several studies suggest that while a fraction of the total extracellular tau is indeed found in exosomes or ectosomes, a large fraction of the extracellular tau pool exists in vesicle-free form [149,155,157,158] (Table 2). Two recent studies demonstrated that tau secretion can occur via a type I mechanism of unconventional protein secretion (UPS I), i.e., by direct translocation across the PM [67,159]. Using complementary methodological approaches, both groups concluded that direct secretion of tau through the PM involves the following key steps: (1) recruitment and clustering of tau at the cytosolic leaflet of the PM involving hyperphosphorylation of tau and specific lipids such as phosphatidyl inositol 4,5 phosphate (PI(4,5)P 2 ) cholesterol and sphingolipids, and (2) release from the PM facilitated by binding to heparan sulfate proteoglycans (HSPG) located at the extracellular leaflet of the PM (Fig.…”

Section: Tau Secretion Directly Through the Plasma Membranementioning

confidence: 99%

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Mechanisms of secretion and spreading of pathological tau protein

Brunello

Merezhko

Uronen

et al. 2019

Cell. Mol. Life Sci.

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209

185

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Accumulation of misfolded and aggregated forms of tau protein in the brain is a neuropathological hallmark of tauopathies, such as Alzheimer's disease and frontotemporal lobar degeneration. Tau aggregates have the ability to transfer from one cell to another and to induce templated misfolding and aggregation of healthy tau molecules in previously healthy cells, thereby propagating tau pathology across different brain areas in a prion-like manner. The molecular mechanisms involved in cell-tocell transfer of tau aggregates are diverse, not mutually exclusive and only partially understood. Intracellular accumulation of misfolded tau induces several mechanisms that aim to reduce the cellular burden of aggregated proteins and also promote secretion of tau aggregates. However, tau may also be released from cells physiologically unrelated to protein aggregation. Tau secretion involves multiple vesicular and non-vesicle-mediated pathways, including secretion directly through the plasma membrane. Consequently, extracellular tau can be found in various forms, both as a free protein and in vesicles, such as exosomes and ectosomes. Once in the extracellular space, tau aggregates can be internalized by neighboring cells, both neurons and glial cells, via endocytic, pinocytic and phagocytic mechanisms. Importantly, accumulating evidence suggests that prion-like propagation of misfolding protein pathology could provide a general mechanism for disease progression in tauopathies and other related neurodegenerative diseases. Here, we review the recent literature on cellular mechanisms involved in cell-to-cell transfer of tau, with a particular focus in tau secretion.

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Section: Tau Secretion Directly Through the Plasma Membranesupporting

confidence: 82%

Section: Tau Secretion Directly Through the Plasma Membranementioning

confidence: 99%

Mechanisms of secretion and spreading of pathological tau protein

Brunello

Merezhko

Uronen

et al. 2019

Cell. Mol. Life Sci.

Self Cite

209

185

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“…In previous studies, it has been proven the seeding nature of Tau as it causes template-dependent aggregation on uptake by healthy neurons [11]. The aggregated extracellular Tau species secreted by various mechanisms have tendency to propagate the disease [41][42][43]. The use of other omega-3 fatty acids DHA, EPA has been studied for the uptake of extracellular Aβ-plaques and their clearance [14,44].…”

Section: Discussionmentioning

confidence: 99%

α-Linolenic acid modulates phagocytosis of extracellular Tau and induces microglial migration

Desale

Chinnathambi

2020

Preprint

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BackgroundSeeding effect of extracellular Tau species is an emerging aspect to study the Tauopathies in Alzheimer's disease. Tau seeds enhance the propagation of disease along with its contribution to microglia-mediated inflammation. Omega-3 fatty acids are known to exert the anti-inflammatory property to microglia by modulating cell membrane compositions. The immunomodulatory function of omega-3 fatty acids exerts anti-inflammatory property to microglia. Owing to the imparted anti-inflammatory nature enhance phagocytosis and increased migration property has been observed in microglia. The dietary omega-3 fatty acids are found to change the lipid composition of the cell membrane that predominated many signaling cascade and by modulating specific receptor response. Thus the omega-3 fatty acids influence microglial response in Tauopathy. MethodsN9 microglia cells were exposed to extracellular full-length Tau monomer and aggregates along with ALA (α-Linolenic acid) to study the internalization of exposed Tau. The degradation of internalized Tau studied with the endosomal markers Rab5 and Rab7. The final degradation step in phagocytosis has been studied with LAMP-2A as lysosomal markers. The changes in the rate of migration of microglia were Author's information Affiliations

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“…Along with the well-established role for PI(4,5)P2 in unconventional secretion of HIV-Tat 30,31 , these findings point at a shared secretory mechanism between FGF2 and HIV-Tat. Furthermore, with Tau and Interleukin 1β, two additional extracellular factors secreted by unconventional means, even more examples have been reported for unconventional secretory processes that depend on PI(4,5)P2 as a prerequisite for their transport into the extracellular space [27][28][29]32 . Thus, after decades of research on unconventional secretory mechanisms in mammalian cells, common features between pathways that are taken by proteins functionally as different as FGF2, Interleukin 1β, Tau and HIV-Tat are beginning to emerge.…”

Section: Discussionmentioning

confidence: 99%

“…For example, a role for PI(4,5)P2 has been reported for unconventional secretion of Tau, HIV-Tat and Interleukin 1β [26][27][28][29][30][31] . In addition, in case of Tau, sulfated glycosaminoglycans on cell surfaces have been shown to have a critical function in trans-cellular spreading that is mediated by unconventional secretion of Tau from donor cells 27,32 .…”

Section: Introductionmentioning

confidence: 99%

The α1 subunit of the Na,K-ATPase acts upstream of PI(4,5)P₂ facilitating unconventional secretion of Fibroblast Growth Factor 2 from tumor cells

Legrand

Saleppico

Sticht

et al. 2019

Preprint

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Fibroblast Growth Factor 2 (FGF2) is a tumor cell survival factor that is exported from cells by an unconventional secretory pathway. This process is based on direct translocation of FGF2 across the plasma membrane. FGF2 membrane translocation depends on PI(4,5)P2-induced formation of membrane-inserted FGF2 oligomers followed by extracellular trapping of FGF2 at the outer leaflet mediated by cell surface heparan sulfate proteoglycans. Beyond the well-characterized core mechanism of FGF2 membrane translocation, the Na,K-ATPase has been proposed to play a so far unknown role in unconventional secretion of FGF2. Here, we define a direct physical interaction of FGF2 with a subdomain of the cytoplasmic part of the α1 subunit of the Na,K-ATPase. Employing NMR spectroscopy and molecular dynamics simulations, we identified two lysine residues on the molecular surface of FGF2 that are shown to be essential for its interaction with α1. In intact cells, the corresponding lysine-to-glutamate variants of FGF2 were characterized by inefficient secretion and reduced recruitment to the inner plasma membrane leaflet as shown by single molecule TIRF microscopy. Our findings suggest that α1 acts upstream of PI(4,5)P2 facilitating efficient membrane translocation of FGF2 to the cell surface of tumor cells.

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Secretion of Tau via an Unconventional Non-vesicular Mechanism

Cited by 135 publications

References 57 publications

Mechanisms of secretion and spreading of pathological tau protein

Mechanisms of secretion and spreading of pathological tau protein

α-Linolenic acid modulates phagocytosis of extracellular Tau and induces microglial migration

The α1 subunit of the Na,K-ATPase acts upstream of PI(4,5)P₂ facilitating unconventional secretion of Fibroblast Growth Factor 2 from tumor cells

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Secretion of Tau via an Unconventional Non-vesicular Mechanism

Cited by 135 publications

References 57 publications

Mechanisms of secretion and spreading of pathological tau protein

Mechanisms of secretion and spreading of pathological tau protein

α-Linolenic acid modulates phagocytosis of extracellular Tau and induces microglial migration

The α1 subunit of the Na,K-ATPase acts upstream of PI(4,5)P2 facilitating unconventional secretion of Fibroblast Growth Factor 2 from tumor cells

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The α1 subunit of the Na,K-ATPase acts upstream of PI(4,5)P₂ facilitating unconventional secretion of Fibroblast Growth Factor 2 from tumor cells