Differentially targeted seeding reveals unique pathological alpha-synuclein propagation patterns.

Parkinson's disease is a progressive neurodegenerative disorder characterized by the intracellular accumulation of insoluble alpha-synuclein aggregates into Lewy bodies and neurites. Increasing evidence indicates that Parkinson's disease progression results from the spread of pathologic alpha-synuclein through neuronal networks. However, the exact mechanisms underlying the propagation of abnormal proteins in the brain are only partially understood. The objective of this study was first to describe the long-term spatiotemporal distributions of Lewy-related pathology in mice injected with alpha-synuclein preformed fibrils and then to recreate these patterns using a computational model that simulates in silico the spread of pathologic alpha-synuclein. In this study, 87 2-3-month-old non-transgenic mice were injected with alpha-synuclein preformed fibrils to generate a comprehensive post-mortem dataset representing the long-term spatiotemporal distributions of hyperphosphorylated alpha-synuclein, an established marker of Lewy pathology, across the 426 regions of the Allen Mouse Brain Atlas. The mice were injected into either the caudoputamen, nucleus accumbens or hippocampus, and followed over 24 months with pathologic alpha-synuclein quantified at seven intermediate time points. The pathologic patterns observed at each time point in this high-resolution dataset were then compared to those generated using a Susceptible-Infected-Removed (SIR) computational model, an agent-based model that simulates the spread of pathologic alpha-synuclein for every brain region taking simultaneously into account the effect of regional brain connectivity and Snca gene expression. Our histopathological findings showed that differentially targeted seeding of pathological alpha-synuclein resulted in unique propagation patterns over 24 months and that most brain regions were permissive to pathology. We found that the SIR model recreated the observed distributions of pathology over 24 months for each injection site. Null models showed that both Snca gene expression and connectivity had a significant influence on model fit. In sum, our study demonstrates that the combination of normal alpha-synuclein concentration and brain connectomics contributes to making brain regions more vulnerable to the pathological process, providing support for a prion-like spread of pathologic alpha-synuclein. We propose that this rich dataset and the related computational model will help test new hypotheses regarding mechanisms that may alter the spread of pathologic alpha-synuclein in the brain.

Predicting longitudinal brain atrophy in Parkinson's disease using a Susceptible-Infected-Removed agent-based model.

Parkinson's disease is a progressive neurodegenerative disorder characterized by accumulation of abnormal isoforms of alpha-synuclein. Alpha-synuclein is proposed to act as a prion in Parkinson's disease: In its misfolded pathologic state, it favors the misfolding of normal alpha-synuclein molecules, spreads trans-neuronally, and causes neuronal damage as it accumulates. This theory remains controversial. We have previously developed a Susceptible-Infected-Removed (SIR) computational model that simulates the templating, propagation, and toxicity of alpha-synuclein molecules in the brain. In this study, we test this model with longitudinal MRI collected over 4 years from the Parkinson's Progression Markers Initiative (1,068 T1 MRI scans, 790 Parkinson's disease scans, and 278 matched control scans). We find that brain deformation progresses in subcortical and cortical regions. The SIR model recapitulates the spatiotemporal distribution of brain atrophy observed in Parkinson's disease. We show that connectome topology and geometry significantly contribute to model fit. We also show that the spatial expression of two genes implicated in alpha-synuclein synthesis and clearance, SNCA and GBA, also influences the atrophy pattern. We conclude that the progression of atrophy in Parkinson's disease is consistent with the prion-like hypothesis and that the SIR model is a promising tool to investigate multifactorial neurodegenerative diseases over time.