?-synuclein-lipoprotein interactions and elevated ApoE level in cerebrospinal fluid from Parkinson's disease patients.

ABSTRACT: The progressive accumulation, aggregation, and spread of ?-synuclein (?SN) are common hallmarks of Parkinson's disease (PD) pathology. Moreover, numerous proteins interact with ?SN species, influencing its toxicity in the brain. In the present study, we extended analyses of ?SN-interacting proteins to cerebrospinal fluid (CSF). Using coimmunoprecipitation, followed by mass spectrometry, we found that ?SN colocalize with apolipoproteins on lipoprotein vesicles. We confirmed these interactions using several methods, including the enrichment of lipoproteins with a recombinant ?SN, and the subsequent uptake of prepared vesicles by human dopaminergic neuronal-like cells. Further, we report an increased level of ApoE in CSF from early PD patients compared with matched controls in 3 independent cohorts. Moreover, in contrast to controls, we observed the presence of ApoE-positive neuromelanin-containing dopaminergic neurons in substantia nigra of PD patients. In conclusion, the cooccurrence of ?SN on lipoprotein vesicles, and their uptake by dopaminergic neurons along with an increase of ApoE in early PD, proposes a mechanism(s) for ?SN spreading in the extracellular milieu of PD.

SUBMITTER: Paslawski W 

PROVIDER: S-EPMC6660770 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature