Cellular milieu imparts distinct pathological α-synuclein strains in α-synucleinopathies

In Lewy body diseases-including Parkinson's disease, without or with dementia, dementia with Lewy bodies, and Alzheimer's disease with Lewy body co-pathology(1)-alpha-synuclein (alpha-Syn) aggregates in neurons as Lewy bodies and Lewy neurites(2). By contrast, in multiple system atrophy alpha-Syn accumulates mainly in oligodendrocytes as glial cytoplasmic inclusions (GCIs)(3). Here we report that pathological alpha-Syn in GCIs and Lewy bodies (GCI-alpha-Syn and LB-alpha-Syn, respectively) is conformationally and biologically distinct. GCI-alpha-Syn forms structures that are more compact and it is about 1,000-fold more potent than LB-alpha-Syn in seeding alpha-Syn aggregation, consistent with the highly aggressive nature of multiple system atrophy. GCI-alpha-Syn and LB-alpha-Syn show no cell-type preference in seeding alpha-Syn pathology, which raises the question of why they demonstrate different cell-type distributions in Lewy body disease versus multiple system atrophy. We found that oligodendrocytes but not neurons transform misfolded alpha-Syn into a GCI-like strain, highlighting the fact that distinct alpha-Syn strains are generated by different intracellular milieus. Moreover, GCI-alpha-Syn maintains its high seeding activity when propagated in neurons. Thus, alpha-Syn strains are determined by both misfolded seeds and intracellular environments.