Abstract
Induction of the antioxidant enzyme heme oxygenase-1 (HO-1) was observed in both astrocytes and neurons in the substantia nigra of patients with Parkinson’s disease (PD). In the current study, we investigated whether HO-1 behaves differently between neurons and astrocytes under the condition of neurotoxicity related to PD. The results showed a time-dependent HO-1 upregulation in primary cultured ventral mesencephalon neurons and astrocytes treated with the mitochondria complex I inhibitor 1-methyl-4-phenylpyridinium (MPP+) or recombinant α-synuclein. However, HO-1 upregulation appeared much later in neurons than in astrocytes. The HO-1 inhibitor zinc protoporphyrin (ZnPP) aggravated MPP+- or α-synuclein-induced oxidative damage in both astrocytes and neurons, indicating that this HO-1 response was cytoprotective. For neurons, the HO-1 activator cobalt protoporphyrin IX (CoPPIX) exerted protective effects against MPP+ or α-synuclein during moderate HO-1 upregulation, but it aggravated damage at the peak of the HO-1 response. For astrocytes, CoPPIXalways showed protective effects. Higher basal and CoPPIX-induced mitochondrial ferritin (MtFt) levels were detected in astrocytes. Lentivirus-mediated MtFt overexpression rescued the neuronal damage induced by CoPPIX, indicating that large MtFt buffering capacity contributes to pronounced HO-1 tolerance in astrocytes. Such findings suggest that astrocyte-targeted HO-1 interventions and MtFt modulations have potential as novel pharmacological strategies in PD.
Highlights
Two genetically distinct isoforms of heme oxygenase (HO) have been described: an inducible form, HO-1, and a constitutively expressed form, HO-218
A significant restoration of ΔΨ m was observed in 25 μmol/L cobalt protoporphyrin IX (CoPPIX)-treated neurons with mitochondria ferritin (MtFt) overexpression compared with that of the lentivector control (Fig. 9b,c). This is the first report to reveal that HO-1 produced different responses in neurons and astrocytes under the condition of neurotoxicity related to Parkinson’s disease (PD)
Despite our limited knowledge of the etiology of PD, it is accepted that oxidative stress causes dopaminergic neuron death because the levels of oxidized lipids, DNA and proteins are increased, and glutathione levels are decreased in the substantia nigra pars compacta (SNpc) of PD patients[6,7,32,33]
Summary
Two genetically distinct isoforms of heme oxygenase (HO) have been described: an inducible form, HO-1, and a constitutively expressed form, HO-218. The HO family catalyzes the rate-limiting step of oxidative degradation of cellular heme into carbon monoxide (CO), bilirubin and free iron[23]. Free iron produced during this catalytic process aggravates cell damage via the Fenton reaction[24,25,26]. This two-sided effect implicates HO-1 as a controversial molecule that acts as a double-edged sword in cell activity and survival[23]. The mechanisms underlying HO-1 actions in neurons and astrocytes remain unknown. We aimed to elucidate the mechanisms underlying the differences in vulnerability to HO-1 modulation between neurons and astrocytes
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