The spread of prion-like proteins by lysosomes and tunneling nanotubes: Implications for neurodegenerative diseases

Victoria, Guiliana Soraya; Zurzolo, Chiara

doi:10.1083/jcb.201701047

Cited by 117 publications

(123 citation statements)

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“…Of interest, TNTs can mediate the transfer of infectious prion particles (Gousset et al, 2009) and other prion-like proteins (Victoria & Zurzolo, 2017). Specifically, we have shown that fibrils of a-synuclein (a-syn), a prion-like protein involved in Parkinson's disease (PD) pathology, can be transferred between neuronal cells (CAD cells) in culture through TNTs (Abounit et al, 2016a).…”

Section: Introductionmentioning

confidence: 99%

The Wnt/Ca ²⁺ pathway is involved in interneuronal communication mediated by tunneling nanotubes

Vargas

Loría

et al. 2019

The EMBO Journal

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Tunneling nanotubes (TNTs) are actin‐based transient tubular connections that allow direct communication between distant cells. TNTs play an important role in several physiological (development, immunity, and tissue regeneration) and pathological (cancer, neurodegeneration, and pathogens transmission) processes. Here, we report that the Wnt/Ca2+ pathway, an intracellular cascade that is involved in actin cytoskeleton remodeling, has a role in TNT formation and TNT‐mediated transfer of cargoes. Specifically, we found that Ca2+/calmodulin‐dependent protein kinase II (CaMKII), a transducer of the Wnt/Ca2+ pathway, regulates TNTs in a neuronal cell line and in primary neurons. We identified the β isoform of CaMKII as a key molecule in modulating TNT formation and transfer, showing that this depends on the actin‐binding activity of the protein. Finally, we found that the transfer of vesicles and aggregated α‐synuclein between primary neurons can be regulated by the activation of the Wnt/Ca2+ pathway. Our findings suggest that Wnt/Ca2+ pathway could be a novel promising target for therapies designed to impair TNT‐mediated propagation of pathogens.

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Section: Introductionmentioning

confidence: 99%

The Wnt/Ca ²⁺ pathway is involved in interneuronal communication mediated by tunneling nanotubes

Vargas

Loría

et al. 2019

The EMBO Journal

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“…Importantly, it was recently reported that the intracellular pool is mainly formed from aggregation-prone, toxic Aβ42, while the less toxic Aβ40 is more abundant extracellularly (Sannerud et al, 2016). Intracellular accumulation of amyloidogenic proteins causes decreased lysosomal efficiency, detected as reduced capacity of degradation, abnormal lysosomal morphology and lysosomal membrane permeabilization as hallmark of neurodegenerative diseases (Freeman et al, 2013;Eriksson et al, 2017;Victoria and Zurzolo, 2017;Gowrishankar et al, 2015). Lysosomes are central hubs for nutrient homeostasis but are also actively involved in cell death induction and PM repair.…”

Section: Oaβ Propagation To Healthy Cells Is Mediated By Transport Inmentioning

confidence: 99%

“…Recently, several studies have demonstrated TNTs to transfer neurodegenerative proteins, such as PrP Sc , α-synuclein, Aβ, tau, polyQ, directly from one cell-to-another (Gousset et al, 2009;Wang et al, 2011;Zhu et al, 2015;Tardivel et al, 2016;Dieriks et al, 2017). Several of these studies implicated links between TNTs and the endo-lysosomal pathway in cell-to-cell spreading (Bhat et al, 2018;Victoria and Zurzolo, 2017). These studies and the discovery of TNTs (Rustom et al, 2004) TNTs are open ended membrane nano-structures with membrane actin protrusions between neighbouring cells.…”

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confidence: 99%

“…A growing number of studies are trying to understand the mechanism behind the formation of TNTs. Some of these studies also reveal that vesicle transfer, recycling vesicles, lysosomes and molecule involved in membrane expansion play a role in the formation of TNTs, the actin membrane protrusions (Bhat et al, 2018;Victoria and Zurzolo, 2017;Hase et al, 2009). Actin depolymerization and actin modulations have been shown to inhibit the formation of these structures (Hanna et al, 2017).…”

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confidence: 99%

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Amyloid-β induced membrane damage instigates tunneling nanotubes by exploiting p21-activated kinase dependent actin remodulation

Öllinger

Kågedal

Nath

2019

Preprint

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The progressive pathology development in Alzheimer's disease is due to direct 12 transfer of amyloid-β1-42 oligomers (oAβ) between connected neurons. However, the 13 mechanism of transfer is not revealed yet. Here we show that internalization of toxic oAβ in 14 SH-SY5Y cells, causes cellular stress detected as significant membrane surface expansion. 15 Subsequently, protrusions appear in the form of tunnelling nanotubes (TNTs). The TNTs 16 propagate oAβ and organelles directly from one cell-to-another. Preceding the formation, we 17 detect oAβ induced plasma membrane damage and repair through lysosomal-exocytosis 18 followed by endocytosis to re-establish the membrane. Eventually, the non-degradable 19 internalized oligomers accumulate in lysosomes. Direct transfer of neurodegenerative proteins 20 via TNTs has recently been suggested as means of pathology spreading. However, molecular 21 basis of TNTs formation is unexplored. The present study is giving the insight that sprouting 22 of TNTs might instigate as consequences of oAβ induced membrane damage and perturbed 23 membrane repair process in the stressed cells, probably to maintain cell surface expansion 24 and/or membrane-tension in equilibrium. 25 26 Summary: TNTs were recently discovered as novel route in cell-to-cell pathology spreading 27 of many diseases. Here we show that TNTs instigate as a consequences of perturbed membrane 28 repair process in oAβ accumulated stressed cells. The mechanistic understanding has enormous 29 pathophysiology significance.30 31 Short title: Direct cell-to-cell transfer of Aβ oligomers in TNTs. 32 33 2

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“…In contrast to other types of neurodegenerative diseases, the infectious and seeding ability is the most distinguishable feature of the Prion disease, which enables the spreading of misfolded prion proteins from peripheral regions to the central nervous system and even interspecies transmissibility (Victoria & Zurzolo, 2017). …”

Section: Introductionmentioning

confidence: 99%

The emerging roles of protein homeostasis‐governing pathways in Alzheimer's disease

et al. 2018

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Pathways governing protein homeostasis are involved in maintaining the structural, quantitative, and functional stability of intracellular proteins and involve the ubiquitin–proteasome system, autophagy, endoplasmic reticulum, and mTOR pathway. Due to the broad physiological implications of protein homeostasis pathways, dysregulation of proteostasis is often involved in the development of multiple pathological conditions, including Alzheimer's disease (AD). Similar to other neurodegenerative diseases that feature pathogenic accumulation of misfolded proteins, Alzheimer's disease is characterized by two pathological hallmarks, amyloid‐β (Aβ) plaques and tau aggregates. Knockout or transgenic overexpression of various proteostatic components in mice results in AD‐like phenotypes. While both Aβ plaques and tau aggregates could in turn enhance the dysfunction of these proteostatic pathways, eventually leading to apoptotic or necrotic neuronal death and pathogenesis of Alzheimer's disease. Therefore, targeting the components of proteostasis pathways may be a promising therapeutic strategy against Alzheimer's disease.

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The spread of prion-like proteins by lysosomes and tunneling nanotubes: Implications for neurodegenerative diseases

Abstract: Victoria and Zurzolo discuss current evidence for the emerging role of lysosomal damage and tunneling nanotubes in the intercellular propagation of prion and prion-like proteins in neurodegenerative disease.

Cited by 117 publications

References 142 publications

The Wnt/Ca ²⁺ pathway is involved in interneuronal communication mediated by tunneling nanotubes

The Wnt/Ca ²⁺ pathway is involved in interneuronal communication mediated by tunneling nanotubes

Amyloid-β induced membrane damage instigates tunneling nanotubes by exploiting p21-activated kinase dependent actin remodulation

The emerging roles of protein homeostasis‐governing pathways in Alzheimer's disease

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The spread of prion-like proteins by lysosomes and tunneling nanotubes: Implications for neurodegenerative diseases

Abstract: Victoria and Zurzolo discuss current evidence for the emerging role of lysosomal damage and tunneling nanotubes in the intercellular propagation of prion and prion-like proteins in neurodegenerative disease.

Cited by 117 publications

References 142 publications

The Wnt/Ca 2+ pathway is involved in interneuronal communication mediated by tunneling nanotubes

The Wnt/Ca 2+ pathway is involved in interneuronal communication mediated by tunneling nanotubes

Amyloid-β induced membrane damage instigates tunneling nanotubes by exploiting p21-activated kinase dependent actin remodulation

The emerging roles of protein homeostasis‐governing pathways in Alzheimer's disease

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The Wnt/Ca ²⁺ pathway is involved in interneuronal communication mediated by tunneling nanotubes

The Wnt/Ca ²⁺ pathway is involved in interneuronal communication mediated by tunneling nanotubes