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Cell Rep. 2015 Mar 3;10(8):1252-60. doi: 10.1016/j.celrep.2015.01.060. Epub 2015 Feb 26.

Progressive aggregation of alpha-synuclein and selective degeneration of lewy inclusion-bearing neurons in a mouse model of parkinsonism.

Author information

1
Jungers Center for Neurosciences Research, Oregon Health and Science University, Portland, OR 97239, USA.
2
Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
3
Department of Pathology, Oregon Health and Science University, Portland, OR 97239, USA.
4
Jungers Center for Neurosciences Research, Oregon Health and Science University, Portland, OR 97239, USA; Parkinson Center of Oregon, Department of Neurology, Oregon Health and Science University, Portland, OR 97239, USA. Electronic address: unni@ohsu.edu.

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.

PMID:
25732816
PMCID:
PMC4351119
DOI:
10.1016/j.celrep.2015.01.060
[Indexed for MEDLINE]
Free PMC Article

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