Transfer of disrupted-in-schizophrenia 1 aggregates between neuronal-like cells occurs in tunnelling nanotubes and is promoted by dopamine

Zhu, Seng; Abounit, Saïda; Korth, Carsten; Zurzolo, Chiara

doi:10.1098/rsob.160328

Cited by 15 publications

(11 citation statements)

References 65 publications

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“…In fact, insoluble aggregates of disrupted‐in‐schizophrenia 1 (DISC1) were associated to sporadic cases of schizophrenia, bipolar disorder, and depression (Korth, 2012; Leliveld et al, 2008). In addition, in vitro studies have demonstrated that aggregates of DISC1 are able to transfer between cells via tunneling nanotubes (Zhu, Abounit, Korth, & Zurzolo, 2017). These aggregates can selectively affect dopaminergic brain functioning at presynaptic and postsynaptic level (Dahoun, Trossbach, Brandon, Korth, & Howes, 2017; Tropea, Hardingham, Millar, & Fox, 2018), and, as they are related to oxidative stress (Trossbach et al, 2016), the transneuronal spread hypothesis is not incompatible with the metabolic stress model.…”

Section: Discussionmentioning

confidence: 99%

Hubs of long‐distance co‐alteration characterize brain pathology

Cauda

Mancuso

Nani

et al. 2020

Human Brain Mapping

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It is becoming clearer that the impact of brain diseases is more convincingly represented in terms of co‐alterations rather than in terms of localization of alterations. In this context, areas characterized by a long mean distance of co‐alteration may be considered as hubs with a crucial role in the pathology. We calculated meta‐analytic transdiagnostic networks of co‐alteration for the gray matter decreases and increases, and we evaluated the mean Euclidean, fiber‐length, and topological distance of its nodes. We also examined the proportion of co‐alterations between canonical networks, and the transdiagnostic variance of the Euclidean distance. Furthermore, disease‐specific analyses were conducted on schizophrenia and Alzheimer's disease. The anterodorsal prefrontal cortices appeared to be a transdiagnostic hub of long‐distance co‐alterations. Also, the disease‐specific analyses showed that long‐distance co‐alterations are more able than classic meta‐analyses to identify areas involved in pathology and symptomatology. Moreover, the distance maps were correlated with the normative connectivity. Our findings substantiate the network degeneration hypothesis in brain pathology. At the same time, they suggest that the concept of co‐alteration might be a useful tool for clinical neuroscience.

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Section: Discussionmentioning

confidence: 99%

Hubs of long‐distance co‐alteration characterize brain pathology

Cauda

Mancuso

Nani

et al. 2020

Human Brain Mapping

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“…is optimal to study TNTs [19,125,[129][130][131]. HeLa cells WT, HeLa cells myrlysin-KO and KIF1B-KIF5B double KO [100,132], and HeLa cells stably expressing Gal3-Turquoise were cultured in DMEM-GlutaMAX including 4.5 g/L D glutamine and pyruvate (Gibco) supplemented with 10% of FBS.…”

Section: Plos Biologymentioning

confidence: 99%

α-Synuclein fibrils subvert lysosome structure and function for the propagation of protein misfolding between cells through tunneling nanotubes

et al. 2021

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The accumulation of α-synuclein (α-syn) aggregates in specific brain regions is a hallmark of synucleinopathies including Parkinson disease (PD). α-Syn aggregates propagate in a “prion-like” manner and can be transferred inside lysosomes to recipient cells through tunneling nanotubes (TNTs). However, how lysosomes participate in the spreading of α-syn aggregates is unclear. Here, by using super-resolution (SR) and electron microscopy (EM), we find that α-syn fibrils affect the morphology of lysosomes and impair their function in neuronal cells. In addition, we demonstrate that α-syn fibrils induce peripheral redistribution of lysosomes, likely mediated by transcription factor EB (TFEB), increasing the efficiency of α-syn fibrils’ transfer to neighboring cells. We also show that lysosomal membrane permeabilization (LMP) allows the seeding of soluble α-syn in cells that have taken up α-syn fibrils from the culture medium, and, more importantly, in healthy cells in coculture, following lysosome-mediated transfer of the fibrils. Moreover, we demonstrate that seeding occurs mainly at lysosomes in both donor and acceptor cells, after uptake of α-syn fibrils from the medium and following their transfer, respectively. Finally, by using a heterotypic coculture system, we determine the origin and nature of the lysosomes transferred between cells, and we show that donor cells bearing α-syn fibrils transfer damaged lysosomes to acceptor cells, while also receiving healthy lysosomes from them. These findings thus contribute to the elucidation of the mechanism by which α-syn fibrils spread through TNTs, while also revealing the crucial role of lysosomes, working as a Trojan horse for both seeding and propagation of disease pathology.

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“…Prions and prion-like proteins were also shown to utilize TNTs for their spreading. Specifically, TNTs were shown to transfer PrP Sc , alpha-synuclein, tau, beta-amyloid, polyglutamine huntingtin and disrupted-in-schizophrenia 1 (DISC1) aggregates [19][20][21][22][23]. Therefore, it has been proposed that by allowing prion-like protein spreading in the brain, TNTs could have a prominent role in the pathogenesis of different neurodegenerative diseases [22].…”

Section: Introductionmentioning

confidence: 99%

Fine intercellular connections in development: TNTs, cytonemes, or intercellular bridges?

Korenkova¹,

Pepe²,

Zurzolo³

2020

CST

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Intercellular communication is a fundamental property of multicellular organisms, necessary for their adequate responses to changing environment. Tunneling nanotubes (TNTs) represent a novel means of intercellular communication being a long cell-to-cell conduit. TNTs are actively formed under a broad range of stresses and are also proposed to exist under physiological conditions. Development is a physiological condition of particular interest, as it requires fine coordination. Here we discuss whether protrusions shown to exist during embryonic development of different species could be TNTs or if they represent other types of cell structure, like cytonemes or intercellular bridges, that are suggested to play an important role in development.

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Transfer of disrupted-in-schizophrenia 1 aggregates between neuronal-like cells occurs in tunnelling nanotubes and is promoted by dopamine

Cited by 15 publications

References 65 publications

Hubs of long‐distance co‐alteration characterize brain pathology

Hubs of long‐distance co‐alteration characterize brain pathology

α-Synuclein fibrils subvert lysosome structure and function for the propagation of protein misfolding between cells through tunneling nanotubes

Fine intercellular connections in development: TNTs, cytonemes, or intercellular bridges?

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