Tunneling nanotube (TNT)-mediated neuron-to neuron transfer of pathological Tau protein assemblies

Tardivel, Meryem; Bégard, Séverine; Bousset, Luc; Dujardin, Simon; Coens, Audrey; Melki, Ronald; Buée, Luc; Colin, Morvane

doi:10.1186/s40478-016-0386-4

Cited by 224 publications

(225 citation statements)

References 72 publications

(82 reference statements)

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“…These include the non-vesicular release of A␤ and ␣-synuclein. Tunneling nanotubes, thin membranous channels formed between cells, have been shown to transfer tau, mutant huntingtin, PrP Sc , and ␣-synuclein between cells (24,90,97,98). These forms of protein transfer may also play a role in the neurodegenerative disease process.…”

Section: Resultsmentioning

confidence: 99%

“…However, this finding was not supported by others who argued that extracellular tau was not found in exosomes (89). Other mechanisms involving tunneling nanotubes have also been suggested to be involved in the transmission of tau between cells (90). Recent discoveries, however, have now clearly implicated exosomes in tau pathology.…”

Section: Extracellular Release Of Taumentioning

confidence: 88%

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Exosomes in the Pathology of Neurodegenerative Diseases

Howitt

Hill

2016

Journal of Biological Chemistry

216

172

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Edited by Paul FraserMore than 30 years ago, two unexpected findings were discovered that challenged conventional thinking in biology. The first was the identification of a misfolded protein with transmissible properties associated with a group of neurodegenerative diseases known as transmissible spongiform encephalopathies. The second was the discovery of a new pathway used for the extracellular release of biomolecules, including extracellular vesicles called exosomes. Two decades later, the convergence of these pathways was shown when exosomes were found to play a significant role in both the transmission and propagation of protein aggregates in disease. Recent research has now revealed that the majority of proteins involved in neurodegenerative diseases are transported in exosomes, and that external stresses due to age-related impairment of protein quality control mechanisms can promote the transcellular flux of these proteins in exosomes. Significantly, exosomes provide an environment that can induce the conformational conversion of native proteins into aggregates that can be transmitted to otherwise aggregate-free cells in the brain. Here we review the current roles of exosomes in the pathology of neurodegenerative diseases.Exosomes are released into the extracellular environment by the majority of cell types in the body. Originally identified to be involved in the non-degradative removal of the transferrin receptor during the maturation process of reticulocytes (1, 2), exosomes have now also been recognized as an important communication and signaling pathway in the body in both normal and disease settings. Exosomes differ from other extracellular vesicles (EVs) 3 based on the secretion pathway used and the size of the vesicle released. Unlike other EVs that can bud from the plasma membrane, such as microvesicles (3), exosomes are created from intraluminal vesicles that form within multivesicular bodies (MVBs, or multivesicular endosomes). The subsequent fusion of the MVB at the plasma membrane releases these vesicles into the extracellular milieu where they are known as exosomes (Fig. 1). This secretion process results in a large number of exosomes being released in the body, with estimates of 3 ϫ 10 6 exosomes per microliter of blood serum. Recent evidence has highlighted the importance of exosomes both for cellular communication and in the delivery of biomolecules.The function of exosomes differs depending on the cell type from which they originate. Initial in vivo studies identified that exosomes derived from dendritic cells could express MHC class II molecules to promote an immune response (4). Since then, exosomes have been found to function in angiogenesis, inflammation, morphogen transportation, and programmed cell death (5). The richest area of exosome research, however, has come from disease studies, in particular the cancer field. Recent evidence has highlighted a role for exosomes to promote metastasis and regulate tumor immune response (6). Of particular interest is the ability of tumors to rel...

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Section: Resultsmentioning

confidence: 99%

Section: Extracellular Release Of Taumentioning

confidence: 88%

Exosomes in the Pathology of Neurodegenerative Diseases

Howitt

Hill

2016

Journal of Biological Chemistry

216

172

View full text Add to dashboard Cite

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“…For instance, the protein Tau was reported to associate with both microtubules and the actin network and to contribute to the formation of TNTs, bridging neurons together [7]. On the other hand, mitochondria were found to traffic along microtubules in PC12 cell-connecting TNTs [8].…”

Section: How Are Tnts Formed? What Are the Tnt-connected Cell Partmentioning

confidence: 99%

Cell Connections by Tunneling Nanotubes: Effects of Mitochondrial Trafficking on Target Cell Metabolism, Homeostasis, and Response to Therapy

Vignais

Caicedo

Brondello

et al. 2017

Stem Cells International

141

163

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Intercellular communications play a major role in tissue homeostasis and responses to external cues. Novel structures for this communication have recently been described. These tunneling nanotubes (TNTs) consist of thin-extended membrane protrusions that connect cells together. TNTs allow the cell-to-cell transfer of various cellular components, including proteins, RNAs, viruses, and organelles, such as mitochondria. Mesenchymal stem cells (MSCs) are both naturally present and recruited to many different tissues where their interaction with resident cells via secreted factors has been largely documented. Their immunosuppressive and repairing capacities constitute the basis for many current clinical trials. MSCs recruited to the tumor microenvironment also play an important role in tumor progression and resistance to therapy. MSCs are now the focus of intense scrutiny due to their capacity to form TNTs and transfer mitochondria to target cells, either in normal physiological or in pathological conditions, leading to changes in cell energy metabolism and functions, as described in this review.

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“…The exact mechanism of transmission is not known. Release and trans-synaptic transmission of tau [164,165], tau uptake via exosomes [166][167][168] or nanotubules [169] and free uptake of fibrillar proteins [170,171] have all been suggested as putative mechanisms using cultured neurons. Although astrocyte-to-neuron intercellular transfer mediated by cell-to-cell contact has been postulated for prions [172], no information is available concerning astrocyte-to-neuron transfer in tauopathies.…”

Section: Disease Progression: Seeding and Spreading; Role Of Astrocytesmentioning

confidence: 99%

Astrogliopathy in Tauopathies

Ferrer

2018

Neuroglia

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Astrocytes are involved in many diseases of the central nervous system, not only as reactive cells to neuronal damage but also as primary actors in the pathological process. Astrogliopathy is a term used to designate the involvement of astrocytes as key elements in the pathogenesis and pathology of diseases and injuries of the central nervous system. Astrocytopathy is utilized to name non-reactive astrogliosis covering hypertrophy, atrophy and astroglial degeneration with loss of function in astrocytes and pathological remodeling, as well as senescent changes. Astrogliopathy and astrocytopathy are hallmarks of tauopathies-neurodegenerative diseases with abnormal hyper-phosphorylated tau aggregates in neurons and glial cells. The involvement of astrocytes covers different disease-specific types such as tufted astrocytes, astrocytic plaques, thorn-shaped astrocytes, granular/fuzzy astrocytes, ramified astrocytes and astrocytes with globular inclusions, as well as others which are unnamed but not uncommon in familial frontotemporal degeneration linked to mutations in the tau gene. Knowledge of molecular differences among tau-containing astrocytes is only beginning, and their distinct functional implications remain rather poorly understood. However, tau-containing astrocytes in certain conditions have deleterious effects on neuronal function and nervous system integrity. Moreover, recent studies have shown that tau-containing astrocytes obtained from human brain tauopathies have a capacity for abnormal tau seeding and spreading in wild type mice. Inclusive conceptions include a complex scenario involving neurons, glial cells and local environmental factors that potentiate each other and promote disease progression in tauopathies.

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Tunneling nanotube (TNT)-mediated neuron-to neuron transfer of pathological Tau protein assemblies

Cited by 224 publications

References 72 publications

Exosomes in the Pathology of Neurodegenerative Diseases

Exosomes in the Pathology of Neurodegenerative Diseases

Cell Connections by Tunneling Nanotubes: Effects of Mitochondrial Trafficking on Target Cell Metabolism, Homeostasis, and Response to Therapy

Astrogliopathy in Tauopathies

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