Cellular Milieu Imparts Distinct Pathological α-Synuclein Strains in α-Synucleinopathies
Chao Peng, Ronald J. Gathagan, Dustin J. Covell, Coraima Medellin, Anna Stieber, John L. Robinson, Bin Zhang, Rose M. Pitkin, Modupe F. Olufemi, Kelvin C. Luk, John Q. Trojanowski, Virginia M.-Y. Lee* The Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104 USA *Corresponding author. email: email@example.com In Lewy body (LB) diseases, including Parkinson's disease (PD), without and with dementia (PDD), dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) patients with LB co-pathology1, α-synuclein (α-Syn) aggregates in neurons as LBs and Lewy neurites (LNs)2, while in multiple system atrophy (MSA), α-Syn mainly accumulates in oligodendrocytes as glial cytoplasmic inclusions (GCIs) 3. Here, we report that pathological α-Syn in GCIs and LBs (GCI-α-Syn and LB-α-Syn) are conformationally and biologically distinct. GCI-α-Syn forms more compact structures and is ~1,000-fold more potent than LB-α-Syn in seeding α-Syn aggregation, consistent with the highly aggressive nature of MSA. Surprisingly, GCI-α-Syn and LB-α-Syn show no cell type preference in seeding α-Syn pathology, raising the question of why they demonstrate different cell type distributions in LB disease versus MSA. Strikingly, we found that oligodendrocytes but not neurons transform misfolded α-Syn into a GCI-like strain, highlighting that distinct α-Syn strains are generated by different intracellular milieus. Moreover, GCI-α-Syn maintains its high seeding activity when propagated in neurons. Thus, α-Syn strains are determined by both misfolded seeds and intracellular environments.
1 Lippa, C. F. et al. Lewy bodies contain altered alpha-synuclein in brains of many familial Alzheimer's disease patients with mutations in presenilin and amyloid precursor protein genes. The American journal of pathology 153, 1365-1370 (1998). 2 Spillantini, M. G. et al. Alpha-synuclein in Lewy bodies. Nature 388, 839-840, doi:10.1038/42166 (1997). 3 Tu, P. H. et al. Glial cytoplasmic inclusions in white matter oligodendrocytes of multiple system atrophy brains contain insoluble alpha-synuclein. Annals of neurology 44, 415-422, doi:10.1002/ana.410440324 (1998).
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