Co-expression of C-terminal truncated alpha-synuclein enhances full-length alpha-synuclein-induced pathology

Authors

  • Ayse Ulusoy,

    1. Brain Repair and Imaging in Neural Systems, Department of Experimental Medical Science, Lund University, BMC D11, 22184, Lund, Sweden
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  • Fabia Febbraro,

    1. Department of Medical Biochemistry, Building 1170, University of Aarhus, Aarhus C DK-8000, Denmark
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  • Poul H. Jensen,

    1. Department of Medical Biochemistry, Building 1170, University of Aarhus, Aarhus C DK-8000, Denmark
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  • Deniz Kirik,

    1. Brain Repair and Imaging in Neural Systems, Department of Experimental Medical Science, Lund University, BMC D11, 22184, Lund, Sweden
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  • Marina Romero-Ramos

    1. Brain Repair and Imaging in Neural Systems, Department of Experimental Medical Science, Lund University, BMC D11, 22184, Lund, Sweden
    2. Department of Medical Biochemistry, Building 1170, University of Aarhus, Aarhus C DK-8000, Denmark
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Ayse Ulusoy, 1Brain Repair and Imaging in Neural Systems, as above.
E-mail: ayse.ulusoy@med.lu.se

Marina Romero-Ramos, 2Department of Medical Biochemistry as above.
E-mail: mrr@biokemi.au.dk

Abstract

Lewy bodies, which are a pathological hallmark of Parkinson’s disease, contain insoluble polymers of alpha-synuclein (αsyn). Among the different modifications that can promote the formation of toxic αsyn species, C-terminal truncation is among the most abundant alterations in patients with Parkinson’s disease. In vitro, C-terminal truncated αsyn aggregates faster and sub-stoichiometric amounts of C-terminal truncated αsyn promote aggregation of the full-length αsyn (αsynFL) and induce neuronal toxicity. To address in vivo the putative stimulation of αsyn-induced pathology by the presence of truncated αsyn, we used recombinant adeno-associated virus to express either αsynFL or a C-terminal truncated αsyn (1-110) in rats. We adjusted the recombinant adeno-associated virus vector concentrations so that either protein alone led to only mild to moderate axonal pathology in the terminals of nigrostriatal dopamine neurons without frank cell loss. When these two forms of αsyn were co-expressed at these pre-determined levels, it resulted in a more aggressive pathology in fiber terminals as well as dopaminergic cell loss in the substantia nigra. Using an antibody that did not detect the C-terminal truncated αsyn (1-110) but only αsynFL, we demonstrated that the co-expressed truncated protein promoted the progressive accumulation of αsynFL and formation of larger pathological accumulations. Moreover, in the co-expression group, three of the eight animals showed apomorphine-induced turning, suggesting prominent post-synaptic alterations due to impairments in the dopamine release, whereas the mild pathology induced by either form alone did not cause motor abnormalities. Taken together these data suggest that C-terminal truncated αsyn can interact with and exacerbate the formation of pathological accumulations containing αsynFL in vivo.

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