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.
Jungers Center for Neurosciences Research, Oregon Health and Science University, Portland, OR 97239, USA.
Valerie R
VR
Osterberg
Jungers Center for Neurosciences Research, Oregon Health and Science University, Portland, OR 97239, USA.
Kateri J
KJ
Spinelli
Jungers Center for Neurosciences Research, Oregon Health and Science University, Portland, OR 97239, USA.
Leah J
LJ
Weston
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.
Kelvin C
KC
Luk
Department of Pathology, Oregon Health and Science University, Portland, OR 97239, USA.
Randall L
RL
Woltjer
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.
Vivek K
VK
Unni
D000368:Aged; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D036681:Fluorescence Recovery After Photobleaching; D005625:Frontal Lobe / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D016631:Lewy Bodies / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology*; D051844:alpha-Synuclein / Q000378:metabolism*
D051844:alpha-Synuclein