The DOI matches its Crossref record; 13 of the 13 references it cites were found in a registry or an index.
Intracerebral inoculation of pathological α-synuclein initiates a rapidly progressive neurodegenerative α-synucleinopathy in mice
Open accessAbstract
The accumulation of misfolded proteins is a fundamental pathogenic process in neurodegenerative diseases. However, the factors that trigger aggregation of α-Synuclein (α-Syn), the principal component of the intraneuronal inclusions known as Lewy bodies (LBs), and Lewy neurites (LNs), which characterize Parkinson’s disease (PD) and dementia with LBs (DLB), are poorly understood. We show here that in young asymptomatic α-Syn transgenic (Tg) mice, intracerebral injections of brain homogenates derived from older Tg mice exhibiting α-Syn pathology accelerate both the formation of intracellular LB/LN-like inclusions and the onset of neurological symptoms in recipient animals. Pathological α-Syn propagated along major central nervous system (CNS) pathways to regions far beyond injection sites and reduced survival with a highly reproducible interval from injection to death in inoculated animals. Importantly, inoculation with α-Syn amyloid fibrils assembled from recombinant human α-Syn induced identical consequences. Furthermore, we show for the first time that synthetic α-Syn fibrils are wholly sufficient to initiate PD-like LBs/LNs and to transmit disease in vivo. Thus, our data point to a prion-like cascade in synucleinopathies whereby cell–cell transmission and propagation of misfolded α-Syn underlie the CNS spread of LBs/LNs. These findings open up new avenues for understanding the progression of PD and for developing novel therapeutics.
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Citations
Cites
Staging of brain pathology related to sporadic Parkinson’s disease
Braak, H., Tredici, K. D., Rüb, U., de Vos, R. A. I., Jansen Steur, E. N. H., & Braak, E. (2003) · Neurobiology of Aging · doi:10.1016/s0197-4580(02)00065-9 · Cited by 10,777
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Transmission and spreading of tauopathy in transgenic mouse brain
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Mice Lacking α-Synuclein Display Functional Deficits in the Nigrostriatal Dopamine System
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Lewy body–like pathology in long-term embryonic nigral transplants in Parkinson's disease
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“…Syn species from dying neurons or by exocytosis represents a more probable source of transmissible Syn (Lee et al., 2008; Desplats et al., 2009; Emmanouilidou et al., 2010; Danzer et al., 2011; Hansen et al., 2011), uptake of which may trigger a reiterative patho genic process like the one…”
BackgroundNeuropathological assessment of Parkinson’s disease: refining the diagnostic criteria
Dickson, D. W., Braak, H., Duda, J. E., Duyckaerts, C., Gasser, T., Halliday, G. M., Hardy, J., Leverenz, J. B., Del Tredici, K., Wszolek, Z. K., et al. (2009) · The Lancet Neurology · doi:10.1016/s1474-4422(09)70238-8 · Cited by 972
Exogenous Induction of Cerebral ß-Amyloidogenesis Is Governed by Agent and Host
Meyer-Luehmann, M., Coomaraswamy, J., Bolmont, T., Kaeser, S., Schaefer, C., Kilger, E., Neuenschwander, A., Abramowski, D., Frey, P., Jaton, A. L., et al. (2006) · Science · doi:10.1126/science.1131864 · Cited by 971
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Prion-like transmission of protein aggregates in neurodegenerative diseases
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Cited by
Kalia, L. V., & Lang, A. E. (2015) · The Lancet · doi:10.1016/s0140-6736(14)61393-3 · Cited by 6,184
Luk, K. C., Kehm, V., Carroll, J., Zhang, B., O’Brien, P., Trojanowski, J. Q., & Lee, V. M.-Y. (2012) · Science · doi:10.1126/science.1227157 · Cited by 2,563
Self-citationThe Role of Oxidative Stress in Parkinson's Disease
Dias, V., Junn, E., & Mouradian, M. M. (2013) · Journal of Parkinson’s Disease · doi:10.3233/jpd-130230 · Cited by 1,845
Self-propagation of pathogenic protein aggregates in neurodegenerative diseases
Jucker, M., & Walker, L. C. (2013) · Nature · doi:10.1038/nature12481 · Cited by 1,663
Goedert, M., Spillantini, M. G., Del Tredici, K., & Braak, H. (2013) · Nature Reviews Neurology · doi:10.1038/nrneurol.2012.242 · Cited by 1,190
Metadata
- Authors
- Luk, K. C., Kehm, V. M., Zhang, B., O’Brien, P., Trojanowski, J. Q., & Lee, V. M. Y.
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2012-04-16
- Volume
- 209
- Issue
- 5
- Pages
- 975-986
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- OpenAlex
- W2131222480
- Cited by
- 1,100
- References
- 13
- FWCI
- 46.93
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Luk, K. C., Kehm, V. M., Zhang, B., O’Brien, P., Trojanowski, J. Q., & Lee, V. M. Y. (2012). Intracerebral inoculation of pathological α-synuclein initiates a rapidly progressive neurodegenerative α-synucleinopathy in mice. Journal of Experimental Medicine. https://doi.org/10.1084/jem.20112457
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