Better explicating the strengths and shortcomings of these models will help refine projections and improve transparency in the years ahead.
Image credit: Witsawat.S.
↵1 P.D. and H.-J.L. contributed equally to this work.
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Edited by Inder M. Verma, The Salk Institute for Biological Studies, La Jolla, CA, and approved June 8, 2009 (received for review April 2, 2009)
Abstract
Neuronal accumulation of α-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 α-synuclein is transmitted via endocytosis to neighboring neurons and neuronal precursor cells, forming Lewy-like inclusions. Moreover, α-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 α-synuclein and inclusion formation. Cells exposed to neuron-derived α-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 α-synuclein aggregates and provide critical insights into the mechanism of pathological progression in PD and other proteinopathies.
Footnotes
- 2To whom correspondence may be addressed. E-mail: emasliah{at}ucsd.edu or sjlee{at}konkuk.ac.kr
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Author contributions: P.D., H.-J.L., E.M., and S.-J.L. designed research; P.D., H.-J.L., E.-J.B., C.P., E.R., L.C., and B.S. performed research; P.D., H.-J.L., E.-J.B., C.P., E.R., L.C., B. S., E.M., and S.-J.L. analyzed data; and P.D., H.-J.L., E.M., and S.-J.L. wrote the paper.
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Edited by Inder M. Verma, The Salk Institute for Biological Studies, La Jolla, CA, and approved June 8, 2009
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Inclusion formation and neuronal cell death through neuron-to-neuron transmission of α-synuclein
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