title: Accelerated proteasomal activity induced by Pb2+, Ga3+, or Cu2+ exposure does not induce degradation of alpha-synuclein.
abstract: The involvement of environmental heavy metals in Parkinson's disease (PD) has been suggested by epidemiologic studies; however, the mechanism of this effect is unknown. PD is characterized by the aggregation of alpha-synuclein in Lewy bodies. We previously showed that Pb2+ accelerates proteasomal activity. Therefore, we examined the effect of Pb2+, Ga3+, and Cu2+ on alpha-synuclein in human SH-SY5Y cells. The heavy metals induced an increase in heme-oxygenase-1 levels without significant cell death or ROS generation. The metals inhibited ALA-dehydratase, which is the inhibitory subunit of the proteasome, thereby accelerating proteasomal activity and decreasing protein levels of CDK-1 and PBGD. However, alpha-synuclein protein levels increased after exposure to metals, similar to the effect obtained with the proteasome inhibitor, hemin, suggesting that alpha-synuclein is inaccessible to proteasomal degradation. Indeed, electron microscopy revealed the formation of aggresomes in Pb2+- or hemin-treated cells. Thus, although heavy metals enhance proteasomal activity, alpha-synuclein is protected from degradation, and its protein levels and aggregation are increased.
authors.affiliation: The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.
authors.forename: Nurit
authors.initials: N
authors.lastname: Grunberg-Etkovitz
authors.forename: Nirit
authors.initials: N
authors.lastname: Lev
authors.forename: Debby
authors.initials: D
authors.lastname: Ickowicz
authors.forename: Almog
authors.initials: A
authors.lastname: Avital
authors.forename: Daniel
authors.initials: D
authors.lastname: Offen
authors.forename: Zvi
authors.initials: Z
authors.lastname: Malik
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D003300:Copper / Q000633:toxicity*; D022083:Cytoplasmic Structures / Q000187:drug effects / Q000648:ultrastructure; D005708:Gallium / Q000633:toxicity*; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006427:Hemin / Q000494:pharmacology; D006801:Humans; D007854:Lead / Q000633:toxicity*; D009154:Mutation; D000623:Porphobilinogen Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects* / Q000648:ultrastructure; D017382:Reactive Oxygen Species / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D051844:alpha-Synuclein; D007854:Lead; D006427:Hemin; D003300:Copper; D005708:Gallium; D051547:Heme Oxygenase-1; D046988:Proteasome Endopeptidase Complex; D000623:Porphobilinogen Synthase