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

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