Transfer of polyglutamine aggregates in neuronal cells occurs in tunneling nanotubes

Costanzo, Maddalena; Abounit, Saïda; Marzo, Ludovica; Danckært, Anne; Chamoun, Zeina; Roux, Pierre; Zurzolo, Chiara

doi:10.1242/jcs.126086

Cited by 171 publications

(191 citation statements)

References 42 publications

(70 reference statements)

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“…Although there is abundant evidence that spreading occurs through synaptic connections, other potential mechanisms include spreading between cells via exosomes (43,44) or tunneling nanotubes (45). In the current study, we find unique patterns of spreading when mutant Htt is expressed in different subsets of neurons in the brain.…”

Section: Discussionmentioning

confidence: 52%

Transcellular spreading of huntingtin aggregates in theDrosophilabrain

Babcock

Ganetzky

2015

Proc. Natl. Acad. Sci. U.S.A.

110

114

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A key feature of many neurodegenerative diseases is the accumulation and subsequent aggregation of misfolded proteins. Recent studies have highlighted the transcellular propagation of protein aggregates in several major neurodegenerative diseases, although the precise mechanisms underlying this spreading and how it relates to disease pathology remain unclear. Here we use a polyglutamineexpanded form of human huntingtin (Htt) with a fluorescent tag to monitor the spreading of aggregates in the Drosophila brain in a model of Huntington's disease. Upon expression of this construct in a defined subset of neurons, we demonstrate that protein aggregates accumulate at synaptic terminals and progressively spread throughout the brain. These aggregates are internalized and accumulate within other neurons. We show that Htt aggregates cause non-cell-autonomous pathology, including loss of vulnerable neurons that can be prevented by inhibiting endocytosis in these neurons. Finally we show that the release of aggregates requires N-ethylmalemide-sensitive fusion protein 1, demonstrating that active release and uptake of Htt aggregates are important elements of spreading and disease progression.

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Section: Discussionmentioning

confidence: 52%

Transcellular spreading of huntingtin aggregates in theDrosophilabrain

Babcock

Ganetzky

2015

Proc. Natl. Acad. Sci. U.S.A.

110

114

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“…However, others 10 also find low proportions of cell-to-cell transfer of TDP-43 aggregates in 2D culture. Moreover, similar experiments with Htt polyQ showed 3.7% of cells had both donor and recipient constructs, 19 indicating that in general these types of experiments have low rates of transfer, likely due to the fact that the culture is 2D and that the cells interface with media and the plastic more than adjacent cells.…”

Section: Discussionmentioning

confidence: 88%

“…Transfer events were quantified as the percentage of transfected cells positive for both tGFP/tdTomato using a similar strategy previously published for Htt. 19 While control cells showed negligible numbers of cells measured as 2 colored (Fig. 2 D), greater than 10% of transfected cells in the co-cultured cell populations contained both fusion proteins at 24 h. The number of cells containing both fusion proteins dropped at 72 h, suggesting that transfer of pathogenic proteins may be particularly toxic.…”

Section: Tdp-43 Can Transfer From Cell-to-cellmentioning

confidence: 91%

Flow cytometric measurement of the cellular propagation of TDP-43 aggregation

Zeineddine

Whiten

Farrawell

et al. 2017

Prion

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ABSTRACT. Amyotrophic lateral sclerosis is a devastating neuromuscular degenerative disease characterized by a focal onset of motor neuron loss, followed by contiguous outward spreading of pathology including TAR DNA-binding protein of 43 kDa (TDP-43) aggregates. Previous work suggests that TDP-43 can move between cells. Here we used a novel flow cytometry technique (FloIT) to analyze TDP-43 inclusions and propagation. When cells were transfected to express either mutant G294A TDP-43 fused to GFP or wild type TDP-43fused to tomato red and then co-cultured, flow cytometry detected intact cells containing both fusion proteins and using FloIT detected an increase in the numbers of inclusions in lysates from cells expressing wild type TDP-43-tomato. Furthermore, in this same model, FloIT analyses detected inclusions containing both fusion proteins. These results imply the transfer of TDP-43 fusion proteins between cells and that this process can increase aggregation of wild-type TDP-43 by a mechanism involving co-aggregation with G294A TDP-43.

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“…133 By contrast, expression of polyQ-HTT fragments in CAD neuronal cells and primary cerebellar granule neurons in vitro did result in spontaneous and efficient transfer to neighboring cells that did not require release from dying cells. 134 In this instance, transfer required cell-to-cell contact and aggregates were found in tunneling nanotubes, which were increased by polyQ-HTT expression. 134 Perhaps providing the most compelling evidence to date of propagation of polyQ-HTT in vitro, a new study has reported that when hESC-derived neurons were introduced into brain slices from HD disease model R6/2 mice, the hESC-derived neurons developed HTT aggregates and exhibited signs of toxicity.…”

Section: Primary Cilia: Secretory Organelles?mentioning

confidence: 91%

“…134 In this instance, transfer required cell-to-cell contact and aggregates were found in tunneling nanotubes, which were increased by polyQ-HTT expression. 134 Perhaps providing the most compelling evidence to date of propagation of polyQ-HTT in vitro, a new study has reported that when hESC-derived neurons were introduced into brain slices from HD disease model R6/2 mice, the hESC-derived neurons developed HTT aggregates and exhibited signs of toxicity. 135 Similarly, when R6/2 cortical brain slices were co-cultured with striatal brain slices from WT mice, polyQ-HTT aggregates developed in the WT striatal neurons.…”

Section: Primary Cilia: Secretory Organelles?mentioning

confidence: 91%

Primary cilia and autophagic dysfunction in Huntington’s disease

2015

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Huntington's disease (HD) is an inherited, neurodegenerative disorder caused by a single-gene mutation: a CAG expansion in the huntingtin (HTT) gene that results in production of a mutated protein, mutant HTT, with a polyglutamine tail (polyQ-HTT). Although the molecular pathways of polyQ-HTT toxicity are not fully understood, because protein misfolding and aggregation are central features of HD, it has long been suspected that cellular housekeeping processes such as autophagy might be important to disease pathology. Indeed, multiple lines of research have identified abnormal autophagy in HD, characterized generally by increased autophagic induction and inefficient clearance of substrates. To date, the origin of autophagic dysfunction in HD remains unclear and the search for actors involved continues. To that end, recent studies have suggested a bidirectional relationship between autophagy and primary cilia, signaling organelles of most mammalian cells. Interestingly, primary cilia structure is defective in HD, suggesting a potential link between autophagic dysfunction, primary cilia and HD pathogenesis. In addition, because polyQ-HTT also accumulates in primary cilia, the possibility exists that primary cilia might play additional roles in HD: perhaps by disrupting signaling pathways or acting as a reservoir for secretion and propagation of toxic, misfolded polyQ-HTT fragments. Here, we review recent research suggesting potential links between autophagy, primary cilia and HD and speculate on possible pathogenic mechanisms and future directions for the field.

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Transfer of polyglutamine aggregates in neuronal cells occurs in tunneling nanotubes

Cited by 171 publications

References 42 publications

Transcellular spreading of huntingtin aggregates in theDrosophilabrain

Transcellular spreading of huntingtin aggregates in theDrosophilabrain

Flow cytometric measurement of the cellular propagation of TDP-43 aggregation

Primary cilia and autophagic dysfunction in Huntington’s disease

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