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

Aminolevulinate dehydratase (δ-ALA-D) as marker protein of intoxication with metals and other pro-oxidant situations

“…12 Recent results indicate that the δ-ALA-D interacts with proteasome and, therefore, could be a physiological modulator of proteasomal activity. Metals that interfere with the δ-ALA-D activity can also change the modulation of proteasome by the δ-ALA-D. [14][15][16][17][18] The toxicological importance of δ-ALA-D inhibition by different metals and by oxidative stress found in a myriad pathological conditions is presented in the next sections of this review.…”

Proteomic changes and molecular effects associated with Cr(III) and Cr(VI) treatments on germinating kiwifruit pollen

“…Heavy metals such as Pb 2+ , Ga 3+ , and Cu 2+ enhanced proteasomal activity in human SH-SY5Y cells (Grunberg-Etkovitz et al, 2009). Furthermore, a proteasome alpha (a)-subunit was found to be over-expressed in the alga Scytosiphon gracilis (Phaeophyceae).…”

Association of Metals and Proteasome Activity in Erythrocytes of Prostate Cancer Patients and Controls

“…In terms of our finding of a positive association between lead and proteasome activity in controls, Grunblat-Etkovitz et al [24] have shown that lead increases proteasome activity in neuroblastoma cell lines and work by Gou et al [25] and Bardag-Gorce et al [2] suggests that delta-aminolevulinic acid dehydratase (ALAD) may interact with the proteasome. ALAD is responsible for the second step of heme synthesis.…”