Dysfunction of mitochondrial complex I and the proteasome: interactions between two biochemical deficits in a cellular model of Parkinson's disease

Abstract

Two biochemical deficits have been described in the substantia nigra in Parkinson's disease, decreased activity of mitochondrial complex I and reduced proteasomal activity. We analysed interactions between these deficits in primary mesencephalic cultures. Proteasome inhibitors (epoxomicin, MG132) exacerbated the toxicity of complex I inhibitors increased free radicals and reduced proteasomal activity via adenosine triphosphate (ATP) depletion. 6-hydroxydopamine also increased free radicals, but did not affect ATP levels and increased proteasomal activity, presumably in response to oxidative damage. Proteasome inhibition potentiated the toxicity of rotenone, MPP + and 6-hydroxydopamine at concentrations at which they increased free radical levels ‡ 40% above baseline, exceeding the cellular capacity to detoxify oxidized proteins reduced by proteasome inhibition, and also exacerbated ATP depletion caused by complex I inhibition. Consistently, both free radical scavenging and stimulation of ATP production by glucose supplementation protected against the synergistic toxicity. In summary, proteasome inhibition increases neuronal vulnerability to normally subtoxic levels of free radicals and amplifies energy depletion following complex I inhibition.

Commitment of 1-Methyl-4-phenylpyrinidinium Ion-induced Neuronal Cell Death by Proteasome-mediated Degradation of p35 Cyclin-dependent Kinase 5 Activator

“…The down-regulation of proteasome activity is detected mainly after longer MPP ϩ treatments, e.g. for ϳ24 h both in cultured cells (40) and mouse brain (41). In these cases, long term treatment with MPP ϩ disrupts mitochondrial complex I activity, resulting in the depletion of ATP.…”

Systemic administration of a proteasome inhibitor does not cause nigrostriatal dopamine degeneration

“…In particular, it appears that UPS dysfunction coupled with other stressors, such as oxidative stress and mitochondrial inhibition, is toxic to nigrostriatal dopamine neurons (Giasson et al, 2000;Hoglinger et al, 2003;Elkon et al, 2004;Betarbet et al, 2005). Although in vitro studies have found that UPS inhibitors can cause dopamine cell death, there has been a lack of data indicating that systemic treatment with UPS inhibitors alone causes specific dopamine neuron toxicity.…”

β-Synuclein Regulates Akt Activity in Neuronal Cells

“…This inhibitor of the mitochondrial complex I was selected because the mitochondrial deficits triggered by this compound are similar to those observed in patients with PD (34). Moreover, this drug promotes selective nigrostriatal dopaminergic degeneration and also causes intracellular accumulation of ␣-synuclein, both characteristic features of PD (13).…”