Cellular milieu imparts distinct pathological ?-synuclein strains in ?-synucleinopathies.

ABSTRACT: 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 -?-synuclein (?-Syn) aggregates in neurons as Lewy bodies and Lewy neurites 2 . By contrast, in multiple system atrophy ?-Syn accumulates mainly in oligodendrocytes as glial cytoplasmic inclusions (GCIs) 3 . Here we report that pathological ?-Syn in GCIs and Lewy bodies (GCI-?-Syn and LB-?-Syn, respectively) is conformationally and biologically distinct. GCI-?-Syn forms structures that are more compact and it is about 1,000-fold more potent than LB-?-Syn in seeding ?-Syn aggregation, consistent with the highly aggressive nature of multiple system atrophy. GCI-?-Syn and LB-?-Syn show no cell-type preference in seeding ?-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 ?-Syn into a GCI-like strain, highlighting the fact that distinct ?-Syn strains are generated by different intracellular milieus. Moreover, GCI-?-Syn maintains its high seeding activity when propagated in neurons. Thus, ?-Syn strains are determined by both misfolded seeds and intracellular environments.

SUBMITTER: Peng C 

PROVIDER: S-EPMC5970994 | biostudies-other | 2018 May

REPOSITORIES: biostudies-other