Journal
PLOS BIOLOGY
Volume 17, Issue 11, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pbio.3000495
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Funding
- Canada First Research Excellence Fund
- Canadian Institutes for Health Research [FDN-143242]
- Natural Sciences and Engineering Research Council of Canada
- Michael J. Fox Foundation
- Weston Brain Institute
- Alzheimer Association
- Natural Sciences and Engineering Research Council of Canada (NSERC) [RGPIN 017-04265]
- Fonds de recherche Quebec-Sante (Chercheur Boursier)
- Canadian Institutes of Health Research (CIHR) [391300]
- Michael J. Fox Foundation for Parkinson's Research
- AbbVie
- Avid
- Bristol-Myers Squibb
- Covance
- GE Healthcare
- GlaxoSmithKline
- Lilly
- Lundbeck
- Meso Scale Discovery
- Pfizer
- Piramal
- Roche
- Sanofi Genzyme
- Servier
- Teva
- UCB
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It is becoming increasingly clear that brain network organization shapes the course and expression of neurodegenerative diseases. Parkinson disease (PD) is marked by progressive spread of atrophy from the midbrain to subcortical structures and, eventually, to the cerebral cortex. Recent discoveries suggest that the neurodegenerative process involves the misfolding and prion-like propagation of endogenous alpha-synuclein via axonal projections. However, the mechanisms that translate local synucleinopathy to large-scale network dysfunction and atrophy remain unknown. Here, we use an agent-based epidemic spreading model to integrate structural connectivity, functional connectivity, and gene expression and to predict sequential volume loss due to neurodegeneration. The dynamic model replicates the spatial and temporal patterning of empirical atrophy in PD and implicates the substantia nigra as the disease epicenter. We reveal a significant role for both connectome topology and geometry in shaping the distribution of atrophy. The model also demonstrates that SNCA and GBA transcription influence alpha-synuclein concentration and local regional vulnerability. Functional coactivation further amplifies the course set by connectome architecture and gene expression. Altogether, these results support the theory that the progression of PD is a multifactorial process that depends on both cell-to-cell spreading of misfolded proteins and regional vulnerability.
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