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

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Abstract

Lewy bodies, which are a pathological hallmark of Parkinson's disease, contain insoluble polymers of alpha-synuclein (alphasyn). Among the different modifications that can promote the formation of toxic alphasyn species, C-terminal truncation is among the most abundant alterations in patients with Parkinson's disease. In vitro, C-terminal truncated alphasyn aggregates faster and sub-stoichiometric amounts of C-terminal truncated alphasyn promote aggregation of the full-length alphasyn (alphasynFL) and induce neuronal toxicity. To address in vivo the putative stimulation of alphasyn-induced pathology by the presence of truncated alphasyn, we used recombinant adeno-associated virus to express either alphasynFL or a C-terminal truncated alphasyn (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 alphasyn 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 alphasyn (1-110) but only alphasynFL, we demonstrated that the co-expressed truncated protein promoted the progressive accumulation of alphasynFL 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 alphasyn can interact with and exacerbate the formation of pathological accumulations containing alphasynFL in vivo.

Details

Authors
  • Ayse Ulusoy
  • Fabia Febbraro
  • Poul H Jensen
  • Deniz Kirik
  • Marina Romero-Ramos
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Neurosciences
Original languageEnglish
Pages (from-to)409-422
JournalEuropean Journal of Neuroscience
Volume32
Issue number3
Publication statusPublished - 2010
Publication categoryResearch
Peer-reviewedYes