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

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. [Display omitted] •Alpha-synuclein fibrils seed conversion of endogenous protein into Lewy pathology•Lewy inclusions undergo a stage-like compaction in vivo•Lewy inclusion-bearing neurons selectively die, whereas non-bearing neurons survive Lewy inclusions are the pathological hallmark of several forms of Parkinsonism and are found in regions where cell loss occurs. However, their relationship to cell death of inclusion-bearing versus non-bearing neurons is not known. Osterberg et al. use in vivo multiphoton imaging in a fibril-seeded mouse model to show selective cell death of inclusion-bearing neurons.