Cited by 1,485Parkinson's Disease Mechanisms and TreatmentsAlzheimer's disease research and treatmentsNuclear Receptors and Signaling

Inclusion formation and neuronal cell death through neuron-to-neuron transmission of α-synuclein

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Desplats, Paula, Lee, He-Jin, Bae, Eun-Jin, Patrick, Christina, Rockenstein, Edward, Crews, Leslie, Spencer, Brian, Masliah, Eliezer +1 more·2009·Proceedings of the National Academy of Sciences

Abstract

Neuronal accumulation of alpha-synuclein and Lewy body formation are characteristic to many neurodegenerative diseases, including Parkinson's disease (PD). This Lewy pathology appears to spread throughout the brain as the disease progresses. Furthermore, recent studies showed the occurrence of Lewy pathology in neurons grafted into the brains of PD patients, suggesting the spread of pathology from the host tissues to the grafts. The mechanism underlying this propagation is unknown. Here, we show that alpha-synuclein is transmitted via endocytosis to neighboring neurons and neuronal precursor cells, forming Lewy-like inclusions. Moreover, alpha-synuclein was transmitted from the affected neurons to engrafted neuronal precursor cells in a transgenic model of PD-like pathology. Failure of the protein quality control systems, especially lysosomes, promoted the accumulation of transmitted alpha-synuclein and inclusion formation. Cells exposed to neuron-derived alpha-synuclein showed signs of apoptosis, such as nuclear fragmentation and caspase 3 activation, both in vitro and in vivo. These findings demonstrate the cell-to-cell transmission of alpha-synuclein aggregates and provide critical insights into the mechanism of pathological progression in PD and other proteinopathies.

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  1. [33]Lee H-J, et al. Neuron-to-glia transmission of α-synuclein causes glial inclusion formation and immune responses in synucleinopathies. J Exp Med. 2009 in press. [Google Scholar]

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Authors
Desplats, P., Lee, H.-J., Bae, E.-J., Patrick, C., Rockenstein, E., Crews, L., Spencer, B., Masliah, E., & Lee, S.-J.
Affiliations
  • University of California San Diego (US)
  • Konkuk University (KR)
  • Seoul National University (KR)
Venue
Proceedings of the National Academy of Sciences
Published
2009-08-04
Volume
106
Issue
31
Pages
13010-13015
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
OpenAlex
W1977267085
Cited by
1,485
References
32
Citations by year
2026: 30 · 2025: 50 · 2024: 60 · 2023: 49 · 2022: 82 · 2021: 96 · 2020: 92 · 2019: 106 · 2018: 98 · 2017: 107 · 2016: 109 · 2015: 106 · 2014: 108 · 2013: 113 · 2012: 106
FWCI
59.11
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Korea Science and Engineering Foundation
  • Ministry of Education, Science and Technology
  • National Institutes of Health (AG5131, AG‐18440, AG10435)
  • National Institute on Aging (P01AG010435, R37AG018440, R01AG018440, P50AG005131, AG-5131, AG 18440, AG02074, AG10435)
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
Keywords
alpha-synuclein, Parkinson's disease, Lewy bodies, cell-to-cell transmission, neuronal precursors, endocytosis, protein aggregation, lysosomal dysfunction, protein quality control, apoptosis, caspase-3, neurodegeneration, proteinopathies, transgenic mouse model
MeSH terms
Animals, Biological Transport, Cell Line, Humans, Mice, Inbred C57BL, Mice, Transgenic, Synaptic Transmission, Neurons, Lewy Bodies, Apoptosis, Stem Cell Transplantation, Mice, Rats, alpha-Synuclein

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