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环境病理学,毒理学和肿瘤学期刊
影响因子: 1.625 5年影响因子: 1.63 SJR: 0.402 SNIP: 0.613 CiteScore™: 2.3

ISSN 打印: 0731-8898
ISSN 在线: 2162-6537

环境病理学,毒理学和肿瘤学期刊

DOI: 10.1615/JEnvironPatholToxicolOncol.v28.i1.20
pages 5-24

Accelerated Proteasomal Activity Induced by Pb2+, Ga3+, or Cu2+ Exposure Does Not Induce Degradation of αt-Synuclein

Nurit Grunberg-Etkovitz
The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel
Nirit Lev
Laboratory of Neuroscience and Department of Neurology, FMRC, Rabin Medical Center, Tel-Aviv University, Petah-Tikva, Israel
Debby Ickowicz
Laboratory of Neuroscience and Department of Neurology, FMRC, Rabin Medical Center, Tel-Aviv University, Petah-Tikva, Israel
Almog Avital
The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel
Daniel Offen
Laboratory of Neuroscience and Department of Neurology, FMRC, Rabin Medical Center, Tel-Aviv University, Petah-Tikva, Israel
Zvi Malik
The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Israel

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 α-synuclein in Lewy bodies. We previously showed that Pb2+ accelerates proteasomal activity. Therefore, we examined the effect of Pb2+, Ga3+, and Cu2+ on α-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, α-synuclein protein levels increased after exposure to metals, similar to the effect obtained with the proteasome inhibitor, hemin, suggesting that α-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, α-synuclein is protected from degradation, and its protein levels and aggregation are increased.


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