A few micrograms of pure, synthetic, aggregated α-synuclein is all it takes to corrupt normal protein in the brain, according to new research. While researchers knew that injecting brain extracts from one diseased rodent into another could seed synuclein pathology, the new study, in the April 16 Journal of Experimental Medicine, is the first to do so with synthetic seeds. In Parkinson’s disease model mice, a single injection of the aggregate was sufficient to speed up age-related pathology in still-healthy animals, killing them within a few months. “It is a direct demonstration that the fibril alone is sufficient to cause this pathology and this spreading,” said senior author Virginia Lee, who led the study with first author Kelvin Luk. Both are at the University of Pennsylvania in Philadelphia.

In people with dementia with Lewy bodies or Parkinson’s, the Lewy bodies and neurites made up of α-synuclein tend to arise in the brainstem and then appear in sequence along a predictable pathway toward the neocortex (Braak et al., 2003). The pathology can even spread to implanted healthy tissue, as it did in the case of grafted fetal embryonic neurons used to treat PD (see ARF related news story on Kordower et al., 2008 and Li et al., 2008). The Lee group and others have shown that α-synuclein inclusions, seeded by recombinant fibrils and oligomers, recruit normal α-synuclein in cultured primary neurons (see ARF related news story and Danzer et al., 2009). In the current work, the team showed that the same happens in vivo in transgenic mice that express human α-synuclein with the PD-associated alanine-53-threonine mutation. These mice normally sicken around one year of age, Lee said.

The team injected brain and spinal cord lysates from sick, aged (more than a year old) mice into the striatum or neocortex of young (two to five months), asymptomatic animals. The α-synuclein pathology quickly extended throughout both sides of the brain, and the animals died approximately 100 days later. Similar tainted-tissue injections can transmit amyloid-β inclusions (see ARF related news story on Eisele et al., 2010 and ARF related news story on Meyer-Luehmann et al., 2006) and tau aggregates (see ARF related news story on Clavaguera et al., 2009). Researchers concluded that amyloidogenic proteins from the donor animals seed new aggregates in the recipients. However, with brain extracts there is “always an element of doubt” because the lysate might contain some secondary factor that promotes disease along with the misfolded protein, noted Lary Walker of Emory University in Atlanta, Georgia, who was not involved with the study.

To dispel that doubt, Luk and colleagues prepared fully synthetic fibrils from recombinant human α-synuclein. When injected into mice, “the response is the same” as with the lysates, Lee said. In fact, “the pathology is more robust.” The inclusions reached more parts of the brain of injected mice than they normally inhabit in these model mice when they age. When the researchers homogenized tissue and measured the amount of detergent-insoluble α-synuclein present, the injected young mice had more than did naturally aging sick mice. In addition to the earlier onset of disease caused by the injection, the progression of pathological inclusions was faster than normal, Lee said, and they died more quickly than the aged version. The pathology probably moves unnaturally quickly because these mice express higher-than-normal concentrations of α-synuclein, Luk said, so injecting the α-synuclein seeds was like putting a match to an oil drum. Animals heterogeneous for the mutant gene had a slower rate of progression following aggregate injection, he told ARF, backing up this explanation. While the disease does not move so quickly in people, Luk noted that people whose familial Parkinson’s is due to extra copies of α-synuclein do have earlier onset and fast progression.

“This is, I would say, proof positive that aggregated α-synuclein does provide a seed for Parkinson’s and Lewy body disease,” said Neil Cashman of the University of British Columbia in Vancouver, who was not involved with the study. “What it demonstrates is that a seeding phenomenon, once kindled, can spread through the brain in a manner that is highly reminiscent of the actual disease.” Researchers have found it more difficult to seed amyloid-β aggregation with recombinant protein, and only recently succeeded with the prions that are the prototype for this kind of malformed protein transmission (Barria et al., 2009; Kim et al., 2010; Marakava et al., 2011). The overall picture thus far indicates that, while amyloid-β and prions require very specific, hard-to-make conformations to convert their normal siblings into something more evil, α-synuclein may readily adopt an infectious form, Cashman suggested.

Luk observed that the aggregates spread to areas of the brain which neurons at the injection site, in Lee’s words, “talk to.” Injection into the striatum produced one reproducible pattern, injection into the neocortex another, each consistent with the site’s position in the neural connectome. Because of this, the researchers think that pathological α-synuclein does not rely on diffusion through parenchyma or cerebrospinal fluid, but instead travels along tracts that conduct the brain’s electrical impulses. The white matter was packed with pathological aggregates, but inclusions also appeared in the cell bodies of gray matter, and the team cannot rule out soma-to-soma transmission, Luk said. The proposed axon-to-dendrite-based mode of transmission for neurodegenerative-linked proteins is “becoming a recurrent theme,” which fits the nature of neurons that are constantly transporting items along their axons and dendrites, Walker said (see ARF Webinar). Scientists have proposed similar modes of travel for viruses (Callaway, 2008) and prions (Scott et al., 1992). Researchers have not quite worked out how the malformed proteins jump from cell to cell, perhaps across synapses; some reports have suggested endocytosis is involved (Desplats et al., 2009; Hansen et al., 2011). By understanding and interfering with that pathway, scientists might be able to halt neurodegeneration in its tracks, Walker suggested.—Amber Dance


  1. This is a very nice paper, and complements the prion-like spreading of Aβ (Meyer-Lühmann et al., 2006) and tau (Clavaguera et al., 2009) in transgenic mice. Strikingly, in the synuclein model, the induced synuclein pathology induces/accelerates neurological symptoms normally seen only in aged synuclein mice. Thus, in a way, the synuclein model is similar to the prion mouse models where inoculations result in a sharp disease endpoint. I am struck that synthetic fibrils also appear to be very active. Data from the prion and Aβ fields would predict that the synthetic material is by far less potent than the brain extract. A little bit surprising is that the authors do not cite previous similar findings, albeit the previous work was less comprehensive (Mougenot et al., 2011).


    . Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host. Science. 2006 Sep 22;313(5794):1781-4. PubMed.

    . Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol. 2009 Jul;11(7):909-13. PubMed.

    . Prion-like acceleration of a synucleinopathy in a transgenic mouse model. Neurobiol Aging. 2011 Aug 1; PubMed.

    View all comments by Mathias Jucker
  2. These results are very exciting indeed. Not only did the authors observe the spread of α-synuclein in areas distal to the injection sites, but they also found the most severe pathology in areas exhibiting dense interconnections. These observations support the Braak hypothesis, which describes the movement of Lewy pathology along known and anatomically connected neuronal pathways in humans.

    View all comments by Patrik Brundin

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News Citations

  1. Dopaminergic Transplants—Stable But Prone to Parkinson’s?
  2. Modeling Sporadic PD in a Dish?
  3. Peripheral Aβ Seeds CAA and Parenchymal Amyloidosis
  4. Double Paper Alert—A Function for BACE, a Basis for Amyloid
  5. Traveling Tau—A New Paradigm for Tau- and Other Proteinopathies?

Webinar Citations

  1. “Network Epicenters” in Healthy Connectome Predict Dementia

Paper Citations

  1. . Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging. 2003 Mar-Apr;24(2):197-211. PubMed.
  2. . Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson's disease. Nat Med. 2008 May;14(5):504-6. PubMed.
  3. . Lewy bodies in grafted neurons in subjects with Parkinson's disease suggest host-to-graft disease propagation. Nat Med. 2008 May;14(5):501-3. PubMed.
  4. . Seeding induced by alpha-synuclein oligomers provides evidence for spreading of alpha-synuclein pathology. J Neurochem. 2009 Oct;111(1):192-203. PubMed.
  5. . Peripherally applied Abeta-containing inoculates induce cerebral beta-amyloidosis. Science. 2010 Nov 12;330(6006):980-2. PubMed.
  6. . Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host. Science. 2006 Sep 22;313(5794):1781-4. PubMed.
  7. . Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol. 2009 Jul;11(7):909-13. PubMed.
  8. . Mammalian prions generated from bacterially expressed prion protein in the absence of any mammalian cofactors. J Biol Chem. 2010 May 7;285(19):14083-7. PubMed.
  9. . Genesis of mammalian prions: from non-infectious amyloid fibrils to a transmissible prion disease. PLoS Pathog. 2011 Dec;7(12):e1002419. PubMed.
  10. . Transneuronal circuit tracing with neurotropic viruses. Curr Opin Neurobiol. 2008 Dec;18(6):617-23. PubMed.
  11. . Scrapie in the central nervous system: neuroanatomical spread of infection and Sinc control of pathogenesis. J Gen Virol. 1992 Jul;73 ( Pt 7):1637-44. PubMed.
  12. . 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.
  13. . α-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells. J Clin Invest. 2011 Feb 1;121(2):715-25. PubMed.

Further Reading


  1. . Beyond α-synuclein transfer: pathology propagation in Parkinson's disease. Trends Mol Med. 2012 May;18(5):248-55. PubMed.
  2. . The amyloid state of proteins in human diseases. Cell. 2012 Mar 16;148(6):1188-203. PubMed.
  3. . A novel, high-efficiency cellular model of fibrillar alpha-synuclein inclusions and the examination of mutations that inhibit amyloid formation. J Neurochem. 2010 Apr;113(2):374-88. PubMed.
  4. . Is Parkinson's disease a prion disorder?. Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):12571-2. PubMed.
  5. . The propagation of prion-like protein inclusions in neurodegenerative diseases. Trends Neurosci. 2010 Jul;33(7):317-25. PubMed.

Primary Papers

  1. . Intracerebral inoculation of pathological α-synuclein initiates a rapidly progressive neurodegenerative α-synucleinopathy in mice. J Exp Med. 2012 May 7;209(5):975-86. PubMed.