The Parkinson Disease-associated A30P Mutation Stabilizes alpha-Synuclein against Proteasomal Degradation Triggered by Heme Oxygenase-1 Overexpression in Human Neuroblastoma Cells.
J Neurochem. 2009 May 13;
Authors: Song W, Patel A, Qureshi HY, Han D, Schipper HM, Paudel HK
Abstract Proteosomal degradation of proteins is one of the major mechanisms of intracellular protein turnover. Failure of the proteosome to degrade misfolded protein is implicated in the accumulation of alpha-synuclein in Parkinson's disease (PD). Heme oxygenase-1 (HO-1), an enzyme that converts heme to free iron, carbon monoxide (CO) and biliverdin (bilirubin precursor), is expressed in response to various stressors. HO-1 is up-regulated in PD- and AD-affected neural tissues. In this study, we found that HO-1 overexpression engenders dose-dependent decreases in alpha-synuclein protein levels in human neuroblastoma M17 cells. When overexpression of HO-1 was silenced in HO-1 transfected cells, level of alpha-synuclein was restored. Likewise, treatment of HO-1 overexpressing cells with the HO-1 inhibitor tin mesoporphyrin, the iron chelator deferoxamine or antagonist of CO-dependent cGMP activation, methylene blue, mitigated the HO-1-induced reduction in alpha-synuclein levels. Furthermore, when HO-1 overexpressing cells were treated with the proteosome inhibitors, lactacystin and MG132, level of alpha-synuclein was almost completely restored. In contrast to the effect on alpha-synuclein (WT) levels, HO-1 overexpression did not significantly impact PD-associated alpha-synuclein (A30P) levels in these cells. HO-1 also significantly reduced aggregation of alpha-synuclein (WT) but not that of A30P. Our results suggest that HO-1, which is expressed when neurons are exposed to toxic stimuli capable of inducing protein misfolding, triggers proteosomal degradation of proteins and prevents intracellular accumulation of protein aggregates and inclusions. Resistance to HO-1 induced proteosomal degradation may render the familial PD-associated A30P mutation prone to toxic intracellular aggregation.
PMID: 19457084 [PubMed - as supplied by publisher]