Cited by 310Parkinson's Disease Mechanisms and TreatmentsAlzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration Mechanisms

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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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Henderson, Michael X., Cornblath, Eli J., Darwich, Adam, Zhang, Bin, Brown, Hannah, Gathagan, Ronald J., Sandler, Raizel M., Bassett, Danielle S., Trojanowski, John Q., Lee, Virginia M. Y.·2019·Nature Neuroscience

DOI 10.1038/s41593-019-0457-5PMC PMC6662627

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Abstract

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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Additional file 1 of Hemispheric asymmetry in the human brain and in Parkinson’s disease is linked to divergent epigenetic patterns in neurons
Li, P., Ensink, E., Lang, S., Marshall, L., Schilthuis, M., Lamp, J. A., Vega, I. E., & Labrie, V. (2020) · Figshare · doi:10.6084/m9.figshare.11960280
Additional file 1 of Trans-synaptic and retrograde axonal spread of Lewy pathology following pre-formed fibril injection in an in vivo A53T alpha-synuclein mouse model of synucleinopathy
Schaser, A. J., Stackhouse, T. L., Weston, L. J., Kerstein, P. C., Osterberg, V. R., López, C. S., Dickson, D. W., Luk, K. C., Meshul, C. K., Woltjer, R. L., et al. (2020) · Figshare · doi:10.6084/m9.figshare.12891207
Additional file 1 of A multiverse of α-synuclein: investigation of prion strain properties with carboxyl-terminal truncation specific antibodies in animal models
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Additional file 10 of Trans-synaptic and retrograde axonal spread of Lewy pathology following pre-formed fibril injection in an in vivo A53T alpha-synuclein mouse model of synucleinopathy
Schaser, A. J., Stackhouse, T. L., Weston, L. J., Kerstein, P. C., Osterberg, V. R., López, C. S., Dickson, D. W., Luk, K. C., Meshul, C. K., Woltjer, R. L., et al. (2020) · Figshare · doi:10.6084/m9.figshare.12891198
Additional file 12 of Hemispheric asymmetry in the human brain and in Parkinson’s disease is linked to divergent epigenetic patterns in neurons
Li, P., Ensink, E., Lang, S., Marshall, L., Schilthuis, M., Lamp, J. A., Vega, I. E., & Labrie, V. (2020) · Figshare · doi:10.6084/m9.figshare.11960274
Additional file 1 of Retina-to-brain spreading of α-synuclein after intravitreal injection of preformed fibrils
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Additional file 2 of Trans-synaptic and retrograde axonal spread of Lewy pathology following pre-formed fibril injection in an in vivo A53T alpha-synuclein mouse model of synucleinopathy
Schaser, A. J., Stackhouse, T. L., Weston, L. J., Kerstein, P. C., Osterberg, V. R., López, C. S., Dickson, D. W., Luk, K. C., Meshul, C. K., Woltjer, R. L., et al. (2020) · Figshare · doi:10.6084/m9.figshare.12891210
Additional file 6 of Trans-synaptic and retrograde axonal spread of Lewy pathology following pre-formed fibril injection in an in vivo A53T alpha-synuclein mouse model of synucleinopathy
Schaser, A. J., Stackhouse, T. L., Weston, L. J., Kerstein, P. C., Osterberg, V. R., López, C. S., Dickson, D. W., Luk, K. C., Meshul, C. K., Woltjer, R. L., et al. (2020) · Figshare · doi:10.6084/m9.figshare.12891222
Additional file 1 of LRRK2 kinase inhibition reverses G2019S mutation-dependent effects on tau pathology progression
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Self-citation
Additional file 7 of Trans-synaptic and retrograde axonal spread of Lewy pathology following pre-formed fibril injection in an in vivo A53T alpha-synuclein mouse model of synucleinopathy
Schaser, A. J., Stackhouse, T. L., Weston, L. J., Kerstein, P. C., Osterberg, V. R., López, C. S., Dickson, D. W., Luk, K. C., Meshul, C. K., Woltjer, R. L., et al. (2020) · Figshare · doi:10.6084/m9.figshare.12891225
Additional file 5 of Trans-synaptic and retrograde axonal spread of Lewy pathology following pre-formed fibril injection in an in vivo A53T alpha-synuclein mouse model of synucleinopathy
Schaser, A. J., Stackhouse, T. L., Weston, L. J., Kerstein, P. C., Osterberg, V. R., López, C. S., Dickson, D. W., Luk, K. C., Meshul, C. K., Woltjer, R. L., et al. (2020) · Figshare · doi:10.6084/m9.figshare.12891219
Additional file 11 of Trans-synaptic and retrograde axonal spread of Lewy pathology following pre-formed fibril injection in an in vivo A53T alpha-synuclein mouse model of synucleinopathy
Schaser, A. J., Stackhouse, T. L., Weston, L. J., Kerstein, P. C., Osterberg, V. R., López, C. S., Dickson, D. W., Luk, K. C., Meshul, C. K., Woltjer, R. L., et al. (2020) · Figshare · doi:10.6084/m9.figshare.12891201
Additional file 3 of Trans-synaptic and retrograde axonal spread of Lewy pathology following pre-formed fibril injection in an in vivo A53T alpha-synuclein mouse model of synucleinopathy
Schaser, A. J., Stackhouse, T. L., Weston, L. J., Kerstein, P. C., Osterberg, V. R., López, C. S., Dickson, D. W., Luk, K. C., Meshul, C. K., Woltjer, R. L., et al. (2020) · Figshare · doi:10.6084/m9.figshare.12891213
Additional file 4 of Trans-synaptic and retrograde axonal spread of Lewy pathology following pre-formed fibril injection in an in vivo A53T alpha-synuclein mouse model of synucleinopathy
Schaser, A. J., Stackhouse, T. L., Weston, L. J., Kerstein, P. C., Osterberg, V. R., López, C. S., Dickson, D. W., Luk, K. C., Meshul, C. K., Woltjer, R. L., et al. (2020) · Figshare · doi:10.6084/m9.figshare.12891216
Additional file 12 of Trans-synaptic and retrograde axonal spread of Lewy pathology following pre-formed fibril injection in an in vivo A53T alpha-synuclein mouse model of synucleinopathy
Schaser, A. J., Stackhouse, T. L., Weston, L. J., Kerstein, P. C., Osterberg, V. R., López, C. S., Dickson, D. W., Luk, K. C., Meshul, C. K., Woltjer, R. L., et al. (2020) · Figshare · doi:10.6084/m9.figshare.12891204
Additional file 9 of Trans-synaptic and retrograde axonal spread of Lewy pathology following pre-formed fibril injection in an in vivo A53T alpha-synuclein mouse model of synucleinopathy
Schaser, A. J., Stackhouse, T. L., Weston, L. J., Kerstein, P. C., Osterberg, V. R., López, C. S., Dickson, D. W., Luk, K. C., Meshul, C. K., Woltjer, R. L., et al. (2020) · Figshare · doi:10.6084/m9.figshare.12891231
Additional file 1 of Effects of local reduction of endogenous α-synuclein using antisense oligonucleotides on the fibril-induced propagation of pathology through the neural network in wild-type mice
Sano, T., Nagata, T., Ebihara, S., Yoshida‐Tanaka, K., Nakamura, A., Sasaki, A., Shimozawa, A., Mochizuki, H., Uchihara, T., Hasegawa, M., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26720163
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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: Henderson, Michael X.
Cornblath, Eli J.
Zhang, Bin
Brown, Hannah
Gathagan, Ronald J.
Bassett, Danielle S.
Trojanowski, John Q.
Lee, Virginia M. Y.
Venue: Nature Neuroscience
Publisher: Springer Science and Business Media LLC
Published: 2019-07-25
Volume: 22
Issue: 8
Pages: 1248-1257
ISSN: 1097-6256 (ISSN-L)
1546-1726
DOI: 10.1038/s41593-019-0457-5
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
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
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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Spread of α-synuclein pathology through the brain connectome is modulated by selective vulnerability and predicted by network analysis

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