Progressive aggregation of alpha-synuclein and selective degeneration of lewy inclusion-bearing neurons in a mouse model of parkinsonism.
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| Abstract |
Aggregated alpha-synuclein inclusions are found where cell death occurs in several diseases, including Parkinson's disease, dementia with Lewy bodies, and multiple-system atrophy. However, the relationship between inclusion formation and an individual cell's fate has been difficult to study with conventional techniques. We developed a system that allows for in vivo imaging of the same neurons over months. We show that intracerebral injection of preformed fibrils of recombinant alpha-synuclein can seed aggregation of transgenically expressed and endogenous alpha-synuclein in neurons. Somatic inclusions undergo a stage-like maturation, with progressive compaction coinciding with decreased soluble somatic and nuclear alpha-synuclein. Mature inclusions bear the post-translational hallmarks of human Lewy pathology. Long-term imaging of inclusion-bearing neurons and neighboring neurons without inclusions demonstrates selective degeneration of inclusion-bearing cells. Our results indicate that inclusion formation is tightly correlated with cellular toxicity and that seeding may be a pathologically relevant mechanism of progressive neurodegeneration in many synucleinopathies.
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| Authors | Valerie R Osterberg, Kateri J Spinelli, Leah J Weston, Kelvin C Luk, Randall L Woltjer, Vivek K Unni |
| Journal | Cell reports (Cell Rep) Vol. 10 Issue 8 Pg. 1252-60 (Mar 03 2015) ISSN: 2211-1247 [Electronic] United States |
| PMID | 25732816 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't) |
| Copyright | Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved. |
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