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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Disease Models, Animal
  • Female
  • Fluorescence Recovery After Photobleaching
  • Frontal Lobe / metabolism
  • Frontal Lobe / pathology
  • Humans
  • Immunohistochemistry
  • Lewy Bodies / metabolism*
  • Lewy Bodies / pathology
  • Male
  • Mice
  • Neurons / metabolism*
  • Neurons / pathology
  • Parkinson Disease / metabolism
  • Parkinson Disease / pathology*
  • alpha-Synuclein / metabolism*


  • alpha-Synuclein