Local vulnerability and global connectivity jointly shape neurodegenerative disease propagation.
Journal
PLoS biology
ISSN: 1545-7885
Titre abrégé: PLoS Biol
Pays: United States
ID NLM: 101183755
Informations de publication
Date de publication:
11 2019
11 2019
Historique:
received:
15
07
2019
accepted:
31
10
2019
revised:
05
12
2019
pubmed:
22
11
2019
medline:
15
2
2020
entrez:
22
11
2019
Statut:
epublish
Résumé
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 α-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 α-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.
Identifiants
pubmed: 31751329
doi: 10.1371/journal.pbio.3000495
pii: PBIOLOGY-D-19-02034
pmc: PMC6894889
doi:
Substances chimiques
alpha-Synuclein
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e3000495Subventions
Organisme : CIHR
ID : FDN-143242
Pays : Canada
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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