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Spread of α-synuclein pathology through the brain connectome is modulated by selective vulnerability and predicted by network analysis
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Studies of patients afflicted by neurodegenerative diseases suggest that misfolded proteins spread through the brain along anatomically connected networks, prompting progressive decline. Recently, mouse models have recapitulated the cell-to-cell transmission of pathogenic proteins and neuron death observed in patients. However, the factors regulating the spread of pathogenic proteins remain a matter of debate due to an incomplete understanding of how vulnerability functions in the context of spread. Here we use quantitative pathology mapping in the mouse brain, combined with network modeling to understand the spatiotemporal pattern of spread. Patterns of α-synuclein pathology are well described by a network model that is based on two factors: anatomical connectivity and endogenous α-synuclein expression. The map and model allow the assessment of selective vulnerability to α-synuclein pathology development and neuron death. Finally, we use quantitative pathology to understand how the G2019S LRRK2 genetic risk factor affects the spread and toxicity of α-synuclein pathology.
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“The arguments for synaptic spread are somewhat weakened by the fact that aggregate spread happens in both antero- and retrograde directions across regions that are anatomical neighbors (68).”
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Metadata
- Authors
- Henderson, M. X., Cornblath, E. J., Darwich, A., Zhang, B., Brown, H., Gathagan, R. J., Sandler, R. M., Bassett, D. S., Trojanowski, J. Q., & Lee, V. M. Y.
- Affiliations
- University of Pennsylvania (US)
- Corresponding author
- Henderson, Michael X.
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2019-07-25
- Volume
- 22
- Issue
- 8
- Pages
- 1248-1257
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC6662627
- OpenAlex
- W2963495948
- Cited by
- 310
- References
- 55
- Citations by year
- 2026: 33 · 2025: 48 · 2024: 47 · 2023: 35 · 2022: 36 · 2021: 42 · 2020: 54 · 2019: 15
- FWCI
- 24.87
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5r01ns099348-04)
- National Institute on Aging (U19AG062418, P30AG010124, T32AG000255)
- National Institute of Neurological Disorders and Stroke (P50NS053488, (R01 NS099348)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- alpha-synuclein pathology, brain connectome, selective neuronal vulnerability, LRRK2 G2019S, neurodegeneration, structural connectivity, network modeling, neuronal cell death, Parkinson's disease
- MeSH terms
- Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Animals, Brain, Brain Mapping, Female, Male, Mice, Inbred C57BL, Models, Neurological, Neurons, Linear Models, Neural Networks, Computer, Cell Death, Mice, alpha-Synuclein, Connectome
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