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

被引:7
|
作者
Gruenberg-Etkovitz, Nurit [1 ]
Lev, Nirit [2 ,3 ]
Ickowicz, Debby [2 ,3 ]
Avital, Almog [1 ]
Offen, Daniel [2 ,3 ]
Malik, Zvi [1 ]
机构
[1] Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, IL-52900 Ramat Gan, Israel
[2] Tel Aviv Univ, Rabin Med Ctr, FMRC, Neurosci Lab, Petah Tiqwa, Israel
[3] Tel Aviv Univ, Rabin Med Ctr, FMRC, Dept Neurol, Petah Tiqwa, Israel
关键词
A53T mutant; heavy metals; heme-oxygenase-1; DELTA-AMINOLEVULINIC-ACID; PARKINSONS-DISEASE; PORPHOBILINOGEN; INHIBITION; EXPRESSION; STRESS; CELLS; NEURODEGENERATION; DEHYDRATASE; NITRATION;
D O I
10.1615/JEnvironPatholToxicolOncol.v28.i1.20
中图分类号
R99 [毒物学(毒理学)];
学科分类号
100405 ;
摘要
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 cc-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, a-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.
引用
收藏
页码:5 / 23
页数:19
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