From the Cover: Manganese and Rotenone-Induced Oxidative Stress Signatures Differ in iPSC-Derived Human Dopamine Neurons

Abstract

Parkinson's disease (PD) is the result of complex interactions between genetic and environmental factors. Two chemically distinct environmental stressors relevant to PD are the metal manganese and the pesticide rotenone. Both are thought to exert neurotoxicity at least in part via oxidative stress resulting from impaired mitochondrial activity. Identifying shared mechanism of action may reveal clues towards an understanding of the mechanisms underlying PD pathogenesis. Here we compare the effects of manganese and rotenone in human-induced pluripotent stem cells-derived postmitotic mesencephalic dopamine neurons by assessing several different oxidative stress endpoints. Manganese, but not rotenone caused a concentration and time-dependent increase in intracellular reactive oxygen/nitrogen species measured by quantifying the fluorescence of oxidized chloromethyl 2',7'-dichlorodihydrofluorescein diacetate (DCF) assay. In contrast, rotenone but not manganese caused an increase in cellular isoprostane levels, an indicator of lipid peroxidation. Manganese and rotenone both caused an initial decrease in cellular reduced glutathione; however, glutathione levels remained low in neurons treated with rotenone for 24 h but recovered in manganese-exposed cells. Neurite length, a sensitive indicator of overall neuronal health was adversely affected by rotenone, but not manganese. Thus, our observations suggest that the cellular oxidative stress evoked by these 2 agents is distinct yielding unique oxidative stress signatures across outcome measures. The protective effect of rasagiline, a compound used in the clinic for PD, had negligible impact on any of oxidative stress outcome measures except a subtle significant decrease in manganese-dependent production of reactive oxygen/nitrogen species detected by the DCF assay.

The Role of Lipids in Parkinson’s Disease

“…Moreover, no changes have been observed in CSF [163] or SN [164] of PD patients, but higher levels of F2-isoprostane have been described in anterior cingulate cortex of PD patients [61]. Higher F2-isoprostane levels have also been observed in rotenone-, but not manganese-treated DA neurons derived from healthy iPSC [165]. Thus, more research and proper stratification of findings need to be performed to understand the role of isoprostanes in PD.…”

Heavy metals contaminating the environment of a progressive supranuclear palsy cluster induce tau accumulation and cell death in cultured neurons

“…Despite some disadvantages, such as the high cost of iPSC generation and a time and labor intensive protocol for neuronal differentiation, human iPSC-derived neurons play an important role in disease modeling and are used to study neurotoxicity of environmental contaminants 50 or chemotherapeutic drugs [51][52][53] . Limiting the utility of iPSCs generated from disease-mutation carriers is the lack of isogenic unaffected controls.…”

Modeling Parkinson’s Disease Using Induced Pluripotent Stem Cells

“…Moreover, different oxidative stress signals produce different molecular effects in SNCA triple iPSCderived DA neurons. Manganese results in a concentrationand time-dependent increase in intracellular ROS/nitrogen species, while rotenone causes an increase in intracellular lipid peroxidation (isoprostane) [25]. Remarkably, in SNCA triplication iPSC-derived cortical neurons, α-synuclein was found to induce endoplasmic reticulum stress by activating the unfolded protein response (UPR) of the IRE1α/XBP1 axis [26].…”