Desplats P, Lee HJ, Bae EJ, Patrick C, Rockenstein E, Crews L, Spencer B, Masliah E, Lee SJ. Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):13010-5. PubMed.

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  1. This paper seems to be interesting, revealing an absolute requirement for intracellular delivery of the fibrillated alpha-synuclein to induce Lewy-body like inclusions. The cell-to-cell communication requires intracellular seeding, which is, however, revealing a pattern similar to prion proteins. Hence the question arises whether alpha-synuclein acts like a prion.

    View all comments by Bharathi Gadad

  2. It was a pleasure to read this work from the Masliah/Lee duo on the cell-to-cell transmission of α-synuclein (Desplats et al., 2009). This work shows that α-synuclein can be released from cells and is taken up by the neighboring cell, thereby aiding in a progressive spread of the protein. This work continues Seung-Jae Lee’s previous work showing that α-synuclein could be released (Lee et al., 2005) and taken up in neurons (Lee et al., 2008; Lee et al., 2008). While the exact mechanism of the release is currently not well defined, this group has done elegant cell biology work to study the internalization mechanism. They show that fluorescently labeled, recombinant α-synuclein is internalized from the extracellular lumen via a dynamin-1-dependent pathway in vitro. This also occurred in vivo, where injection of GFP-labeled mouse cortical neuronal stem cells into the hippocampus of α-synuclein-transgenic mice led to the efficient uptake of the host α-synuclein into the grafted stem cells after just four weeks. These data add yet another case to the growing list of host-graft relationships in amyloid disorders.

    Desplats et al. go on to demonstrate that the internalized α-synuclein promotes inclusion body-like structures in the cytosol of the acceptor cells that are positive for ubiquitin and thioflavin S. This somehow depends on the integrity of lysosomes, as lysosomal pH disruption using v-ATPase inhibitors aggravates the inclusion body formation. How lysosomal function is coupled to a process that occurs in the cytosol is not clear, but the authors rule out membrane leakage. The last figure in the paper gives the take-home message, where the authors demonstrate neurodegeneration in both primary neurons and the mouse cortical stem cells that were exposed to neuronal cell-derived extracellular α-synuclein. This suggests that the released and internalized α-synuclein could be responsible for progression and pathology.

    Seeding and spreading are not new features of neurodegenerative diseases (Aβ, e.g., Meyer-Luehmann. et al., 2006; prions, e.g., Bolton et al., 1982). But this time it is different. Three cytoplasmic proteins, as opposed to lumenally exposed membrane proteins, have been recently documented to show this effect. Work from Lee’s group has shown that α-synuclein can be exocytosed from cells. And recently, tau, another cytoplasmic protein of immediate interest to this community because of its involvement in AD and FTD, was shown also to act from outside (Clavaguera et al., 2009). Moreover, polyglutamine aggregates, which are relevant to Huntington disease, are internalized into the cytosol as well (Ren et al., 2009). Several features in this work open up new questions:

    1. How are these cytosolic proteins released to the extracellular space (“cytosol to lumen” paradox)? Is the release regulated? Is it only the aggregated versions of the protein, or could the monomeric proteins also be secreted?

    2. How does internalized extracellular α-synuclein end up in the cytoplasm (“lumen to cytosol” paradox)? Desplats et al. show that the internalization occurs via endocytosis, but how does the protein enter the cytosol from the endosomes? The authors show that the internalized α-synuclein initiates a Lewy body-like inclusion in the cytosol.

    3. In the case of the α-synucleinopathies, the pathology spreads progressively to remote areas of the brain. This work could contribute to the direct understanding of this spreading. On the other hand, in tau pathology, similar spreading occurs (from the transentorhinal cortex to the hippocampus), and again a cytoplasmic protein is released or injected that contributes to the spread of the pathology.

    4. How does the spreading occur? Nanotubes could be one way. Prions hijack tunneling nanotubes during their intercellular spreading (Gousset et al., 2009). Though Desplats et al. show that recombinant α-synuclein (and also Ren et al. in the case of polyQ) could enter cells from the extracellular space, nanotubes may aid in the spreading and progression.

    5. That a toxic protein would instruct amyloid formation in the wild-type counterpart (be it in the host or graft) on one hand is alarming as it raises caution about stem cell therapies. But on the other, it unfolds a new paradigm in the amyloid pathogenesis. An insightful commentary by Adriano Aguzzi (2009) suggests that many proteins could act like prions; Aguzzi calls them prionoids. Certainly a body of recent work points in this direction. Such studies could be extended to other neurodegenerative amyloid disorders to see if this could be generalized.

    One thing is clear. The gap between cell biology and neuroscience is narrowing. Exciting times are to come where we will use cell biology not just for basic understanding of these diseases, but, as shown in the current work, also for therapeutic deliberations.

    References:

    Lee HJ, Patel S, Lee SJ. Intravesicular localization and exocytosis of alpha-synuclein and its aggregates. J Neurosci. 2005 Jun 22;25(25):6016-24. PubMed.

    Lee HJ, Suk JE, Bae EJ, Lee JH, Paik SR, Lee SJ. Assembly-dependent endocytosis and clearance of extracellular alpha-synuclein. Int J Biochem Cell Biol. 2008;40(9):1835-49. PubMed.

    Lee HJ, Suk JE, Bae EJ, Lee SJ. Clearance and deposition of extracellular alpha-synuclein aggregates in microglia. Biochem Biophys Res Commun. 2008 Aug 1;372(3):423-8. PubMed.

    Meyer-Luehmann M, Coomaraswamy J, Bolmont T, Kaeser S, Schaefer C, Kilger E, Neuenschwander A, Abramowski D, Frey P, Jaton AL, Vigouret JM, Paganetti P, Walsh DM, Mathews PM, Ghiso J, Staufenbiel M, Walker LC, Jucker M. Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host. Science. 2006 Sep 22;313(5794):1781-4. PubMed.

    Bolton DC, McKinley MP, Prusiner SB. Identification of a protein that purifies with the scrapie prion. Science. 1982 Dec 24;218(4579):1309-11. PubMed.

    Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S, Probst A, Fraser G, Stalder AK, Beibel M, Staufenbiel M, Jucker M, Goedert M, Tolnay M. Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol. 2009 Jul;11(7):909-13. PubMed.

    Ren PH, Lauckner JE, Kachirskaia I, Heuser JE, Melki R, Kopito RR. Cytoplasmic penetration and persistent infection of mammalian cells by polyglutamine aggregates. Nat Cell Biol. 2009 Feb;11(2):219-25. PubMed.

    Gousset K, Schiff E, Langevin C, Marijanovic Z, Caputo A, Browman DT, Chenouard N, de Chaumont F, Martino A, Enninga J, Olivo-Marin JC, Männel D, Zurzolo C. Prions hijack tunnelling nanotubes for intercellular spread. Nat Cell Biol. 2009 Mar;11(3):328-36. Epub 2009 Feb 8 PubMed.

    Aguzzi A. Cell biology: Beyond the prion principle. Nature. 2009 Jun 18;459(7249):924-5. PubMed.

    View all comments by Lawrence Rajendran

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