Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats
- 7.1k Downloads
The cellular hallmarks of Parkinson’s disease (PD) are the loss of nigral dopaminergic neurons and the formation of α-synuclein-enriched Lewy bodies and Lewy neurites in the remaining neurons. Based on the topographic distribution of Lewy bodies established after autopsy of brains from PD patients, Braak and coworkers hypothesized that Lewy pathology primes in the enteric nervous system and spreads to the brain, suggesting an active retrograde transport of α-synuclein (the key protein component in Lewy bodies), via the vagal nerve. This hypothesis, however, has not been tested experimentally thus far. Here, we use a human PD brain lysate containing different forms of α-synuclein (monomeric, oligomeric and fibrillar), and recombinant α-synuclein in an in vivo animal model to test this hypothesis. We demonstrate that α-synuclein present in the human PD brain lysate and distinct recombinant α-synuclein forms are transported via the vagal nerve and reach the dorsal motor nucleus of the vagus in the brainstem in a time-dependent manner after injection into the intestinal wall. Using live cell imaging in a differentiated neuroblastoma cell line, we determine that both slow and fast components of axonal transport are involved in the transport of aggregated α-synuclein. In conclusion, we here provide the first experimental evidence that different α-synuclein forms can propagate from the gut to the brain, and that microtubule-associated transport is involved in the translocation of aggregated α-synuclein in neurons.
KeywordsParkinson’s disease Alpha-synuclein Lewy body Protein aggregation Protein propagation
The authors wish to thank Marianne Juhlin and AnnaKarin Oldén for their excellent technical support. We thank Andrew C. McCourt for the linguistic revision of this manuscript. This work was funded by grants from the Swedish Research Council; Torsten Söderberg Foundation and Swedish Parkinson Foundation (J.-Y. L.). S.H., O.C., T.A., L.R. and J.-Y. L are active and supported by BAGADILICO—Excellence in Parkinson and Huntington Research, and the Strategic Research Area Multipark (Multidisciplinary research in Parkinson’s disease at Lund University); L.B. and R.M. are supported by the Centre National de la Recherche Scientifique and Grants from the Agence Nationale de la Recherche (ANR-11-BSV8-021-01) and a ‘Coup d’Elan a la Recherche Francaise’ award from Fondation Bettencourt Schueller. Z.Y.W. and J.-Y.L. are supported by National Natural Science Foundation of China (81430025) and the Fundamental Research Funds for Central Universities of China (N130120002).
Conflict of interest
The authors declare no competing financial interests.
- 15.Hansen C, Angot E, Bergstrom AL, Steiner JA, Pieri L, Paul G, Outeiro TF, Melki R, Kallunki P, Fog K et al (2011) alpha-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells. J Clin Invest 121:715–725. doi: 10.1172/JCI43366 PubMedCentralPubMedCrossRefGoogle Scholar
- 30.Li JY, Englund E, Widner H, Rehncrona S, Bjorklund A, Lindvall O, Brundin P (2010) Characterization of Lewy body pathology in 12- and 16-year-old intrastriatal mesencephalic grafts surviving in a patient with Parkinson’s disease. Mov Disord 25:1091–1096. doi: 10.1002/mds.23012 PubMedCrossRefGoogle Scholar
- 36.Pan-Montojo F, Schwarz M, Winkler C, Arnhold M, O’Sullivan GA, Pal A, Said J, Marsico G, Verbavatz JM, Rodrigo-Angulo M et al (2012) Environmental toxins trigger PD-like progression via increased alpha-synuclein release from enteric neurons in mice. Sci Rep 2:898. doi: 10.1038/srep00898 PubMedCentralPubMedCrossRefGoogle Scholar
- 38.Parkkinen L, Pirttila T, Alafuzoff I (2008) Applicability of current staging/categorization of alpha-synuclein pathology and their clinical relevance. Acta Neuropathol 115(4):399–407Google Scholar
- 42.Recasens A, Dehay B, Bove J, Carballo-Carbajal I, Dovero S, Perez-Villalba A, Fernagut PO, Blesa J, Parent A, Perier C et al (2014) Lewy body extracts from Parkinson disease brains trigger alpha-synuclein pathology and neurodegeneration in mice and monkeys. Ann Neurol 75:351–362. doi: 10.1002/ana.24066 PubMedCrossRefGoogle Scholar
- 48.Snapp EL, Altan N, Lippincott-Schwartz J (2003) Measuring protein mobility by photobleaching GFP chimeras in living cells. Curr Protoc Cell Biol. doi: 10.1002/0471143030.cb2101s19