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

ValerieR Osterberg, KateriJ Spinelli, LeahJ Weston, KelvinC Luk, Randall (Randy) Woltjer, Vivek Unni

Research output: Contribution to journalArticle

81 Citations (Scopus)

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

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Bearings (structural)
alpha-Synuclein
Parkinsonian Disorders
Neurons
Agglomeration
Multiple System Atrophy
Lewy Body Disease
Parkinson Disease
Seeds
Cell Death
Pathology
Imaging techniques
Injections
Cell death
Toxicity
Seed
Compaction

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Progressive Aggregation of Alpha-Synuclein and Selective Degeneration of Lewy Inclusion-Bearing Neurons in a Mouse Model of Parkinsonism. / Osterberg, ValerieR; Spinelli, KateriJ; Weston, LeahJ; Luk, KelvinC; Woltjer, Randall (Randy); Unni, Vivek.

In: Cell Reports, Vol. 10, No. 8, 03.03.2015, p. 1252-1260.

Research output: Contribution to journalArticle

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