Soluble and Insoluble Lysates from the Human A53T Mutant α-Synuclein Transgenic Mouse Model Induces α-Synucleinopathy...

Pathological aggregation of α-synuclein (αS) is implicated in the pathogenesis of Parkinson's disease (PD) and other α-synucleinopathies. The current view is that neuron-to-neuron spreading of αS pathology contributes to the progression of α-synucleinopathy. We used an A53T mutant human αS transgenic mouse model (TgA53T) to examine whether the site of pathogenic αS inoculation affects the pattern of neuropathology and whether soluble and insoluble fractions derived from crude pathogenic tissue lysates exhibit differential capacities to initiate αS pathology. To test whether the inoculation site impacts the ultimate spatial/temporal patterns of αS pathology, αS preformed fibrils (PFFs), or brain homogenates from TgA53T mice with α-synucleinopathy, were injected into the cortex/striatum, brainstem, or skeletal muscle. In all cases, inoculation of pathogenic αS induced end-stage motor dysfunction within ~100 days post-inoculation (dpi). Significantly, irrespective of the inoculation sites, the ultimate distribution of the αS pathology was like that seen in normally aged TgA53T mice at end-stage, indicating that the intrinsic neuronal vulnerability is a significant determinant in the induction of αS pathology, even when initiated by inoculation of pathogenic αS. Temporal analysis of brainstem-injected TgA53T mice show that initial αS pathology was seen by 30 days post-inoculation and inflammatory changes occur at later stages. In addition, we show that both highly soluble (S150) and insoluble (P150) fractions from end-stage TgA53T mice can seed de novo αS pathology in vivo. Moreover, the endoplasmic reticulum (ER)-enriched fraction from the TgA53T mice were highly pathogenic as the ER fraction induced αS pathology faster than other fractions when injected unilaterally into TgA53T mice. Our results suggest that multiple αS species from the brain can initiate the development of progressive αS pathology.