Abstract
The pathogenesis of Parkinson's disease involves fibrillization and deposition of alpha-synuclein (α-syn) into Lewy bodies. Accumulating evidence suggests that α-syn oligomers are particularly neurotoxic. Transgenic (tg) mice overexpressing wild-type human α-syn under the Thy-1 promoter (L61) reproduce many Parkinson's disease features, but the pathogenetic relevance of α-syn oligomers in this mouse model has not been studied in detail. Here, we report an age progressive increase of α-syn oligomers in the brain of L61 tg mice. Interestingly, more profound motor symptoms were observed in animals with higher levels of membrane-bound oligomers. As this tg model is X-linked, we also performed subset analyses, indicating that both sexes display a similar age-related increase in α-syn oligomers. However, compared with females, males featured increased brain levels of oligomers from an earlier age, in addition to a more severe behavioral phenotype with hyperactivity and thigmotaxis in the open field test. Taken together, our data indicate that α-syn oligomers are central to the development of brain pathology and behavioral deficits in the L61 tg α-syn mouse model.
Highlights
The progressive accumulation of a-synuclein (a-syn) into insoluble fibrillar inclusions known as Lewy bodies and Lewy neurites is central to the pathogenesis of Parkinson's disease (PD)
To assess the effect of age progression on a-syn aggregation, we measured the levels of a-syn in sequentially extracted protein fractions of decreasing solubility (TBS, tris-buffered saline (TBS)-T and FA soluble fractions, for details see Supplementary Fig.1)
As soluble a-syn oligomers are considered neurotoxic, we analyzed the ratio of less soluble species (TBS-T fraction) versus TBS soluble a-syn (Fig. 1F)
Summary
The progressive accumulation of a-synuclein (a-syn) into insoluble fibrillar inclusions known as Lewy bodies and Lewy neurites is central to the pathogenesis of Parkinson's disease (PD)and other a-synucleinopathies. Alpha-synuclein is a small, evolutionarily conserved protein and its gene, SNCA, is abundantly expressed in the central nervous system. It is enriched in presynaptic terminals (Maroteaux et al, 1988; Kahle & et al, 2000; Yang & et al, 2010) and mediates its cellular function by interacting with synaptic vesicle membranes (Burre, 2015). Cytosolic a-syn shifts from a natively unfolded and unstructured state to a membrane-bound, alphahelical structure (Burré et al, 2014). The intrinsic properties of a-syn allow for a shift of its conformation into a pathogenic state, with self-assembly into b-sheeterich structures that promote the formation of oligomers, protofibrils, and eventually fibrils
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