Luk KC, Kehm VM, Zhang B, O'Brien P, Trojanowski JQ, Lee VM.
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.
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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 A little bit surprising is that the authors do not cite previous similar findings, albeit the previous work was less comprehensive (Mougenot et al., 2011).
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.
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.
Mougenot AL, Nicot S, Bencsik A, Morignat E, Verchère J, Lakhdar L, Legastelois S, Baron T.
Prion-like acceleration of a synucleinopathy in a transgenic mouse model.
Neurobiol Aging. 2011 Aug 1;
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.