Soluble and insoluble lysates from the human A53T mutant α-synuclein transgenic mouse model induces α-synucleinopathy independent of injection site

TL;DR

This study shows that injecting different forms of alpha-synuclein from a mouse model can cause Parkinson's-like brain changes regardless of where it's injected.

Contribution

Demonstrates that alpha-synuclein pathology spreads based on brain vulnerability, not injection site, and that both soluble and insoluble forms can initiate disease.

Findings

Inoculation of pathogenic alpha-synuclein in different brain regions or muscle leads to similar end-stage pathology patterns.

Both soluble and insoluble alpha-synuclein fractions can seed new pathology, with ER-enriched fractions being most pathogenic.

Inflammatory changes occur at later stages after alpha-synuclein inoculation in the brain stem.

Abstract

Pathological aggregation of a-synuclein (aS) is implicated in the pathogenesis of Parkinson’s disease (PD) and other a-synucleinopathies. The current view is that neuron-to-neuron spreading of aS pathology contributes to the progression of a-synucleinopathy. We used an A53T mutant human aS transgenic mouse model (TgA53T) to examine whether the site of pathogenic aS inoculation affects the pattern of neuropathology and whether soluble and insoluble fractions derived from crude pathogenic tissue lysates exhibit differential capacities to initiate aS pathology. To test whether the inoculation site impacts the ultimate spatial/temporal patterns of aS pathology, aS preformed fibrils (PFF), or brain homogenates from TgA53T mice with a-synucleinopathy, were injected into the cortex/striatum, brain stem, or skeletal muscle. In all cases, inoculation of pathogenic aS induced end-stage motor dysfunction within ~100 days post-inoculation (dpi). Significantly, irrespective of the inoculation sites, ultimate distribution of the aS 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 aS pathology, even when initiated by inoculation of pathogenic aS. Temporal analysis of brain stem injected TgA53T mice show that initial aS pathology was seen by 30 days post-inoculation and inflammatory changes occur at later stages. To determine if the aS species with differential solubility are differentially pathogenic, brain lysates from end-stage TgA53Tmice were fractionated into highly soluble (S150) and insoluble (P150) fractions, as well as the endoplasmic reticulum (ER)-enriched fraction (P100). Significantly, all fractions were able to seed de novo aS pathology in vivo, when injected unilaterally into TgA53Tmice with the ER fractions being most pathogenic. Our results suggest that multiple aS species from brain can initiate the development of progressive aS pathology.

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