Progressive Aggregation of Alpha-Synuclein and Selective Degeneration of Lewy Inclusion-Bearing Neurons in a Mouse Model of Parkinsonism

Valerie R. Osterberg, Kateri J. Spinelli, Leah J. Weston, Kelvin C. Luk, Randall L. Woltjer, Vivek K. Unni

Research output: Contribution to journalArticle

95 Scopus citations

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 invivo 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.

Original languageEnglish (US)
Pages (from-to)1252-1260
Number of pages9
JournalCell Reports
Volume10
Issue number8
DOIs
StatePublished - Mar 3 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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