Metabolic enzyme expression in dopaminergic neurons in Parkinson's disease: An in situ hybridization study

Abstract

To clarify the role of neuronal complex 1 activity in idiopathic Parkinson's disease (IPD), expression of mitochondrial mRNA encoding the ND1 subunit of mitochondrial complex I was examined by semiquantitative in situ hybridization histochemistry in melanized neurons of human substantia nigra in IPD cases and control subjects. Expression of mRNA encoding the glycolytic enzyme, aldolase C, was also examined in substantia nigra and other neurons of the midbrain and brain stem. ND1 mRNA expression was strong in melanized substantia nigra neurons but undetectable in nigral glia. Levels of expression in nigral neurons were higher than in neurons of the red nucleus or cranial nerve nuclei, but similar values were obtained in pontine neurons. ND1 mRNA expression was reduced by about 25% in melanized neurons in IPD. There was no relationship between ND1 expression per cell and disease duration or L-DOPA dosage in the IPD group. No change in ND1 expression was observed in pontine neurons in IPD, and ND1 expression in the locus ceruleus was also unchanged. Melanized nigral neurons expressed lower levels of aldolase C mRNA than other midbrain or brain stem populations in both control and IPD material. These findings suggest that dopamine neurons are more strongly dependent on mitochondrial energy metabolism and oxidative phosphorylation than other brain stem populations. Because mitochondrial complex I activity is significantly reduced in IPD, intrinsically low expression of glycolytic enzymes, together with disease-related reduction in complex I activity, may be a contributory factor predisposing nigral neurons

Effects of Ginkgo biloba extract (EGb 761) on gene expression: Possible relevance to neurological disorders and age‐associated cognitive impairment

“…This view is supported by a recent study, performed using in situ hybridization histochemistry, which showed that mitochondrial ND1 mRNA expression is decreased in neuromelanin-containing substantia nigra neurons of patients with idiopathic PD (IPD), as compared to control subjects [Kingsbury et al, 2001]. As this decrease in mitochondrial Complex I activity in IPD may be involved in predisposing nigral neurons to degeneration, EGb 761 or bilobalide (by increasing the expression of ND1) could possibly be useful in preventing or delaying the progression of neurodegeneration in this disease.…”

“…With specific regard to the study of Tendi et al [2002], their findings that EGb 761 and bilobalide increased the expression of the gene encoding ND1 could be relevant to developing therapy for PD, since oxidative stress and a selective defect in Complex I of OXPHOS (which is encoded by both mtDNA and nDNA) have been implicated in the progressive cell loss (mainly in dopaminergic neurons of the substantia nigra) that occurs in a subset of patients with this neurodegenerative disorder [see e.g., Przedborski et al, 1993;Swerdlow et al, 1996;Anglade et al, 1997;Kosel et al, 1998;Pettus et al, 2000;Chinopoulos and Adam-Vizi, 2001;Kingsbury et al, 2001]. This view is supported by a recent study, performed using in situ hybridization histochemistry, which showed that mitochondrial ND1 mRNA expression is decreased in neuromelanin-containing substantia nigra neurons of patients with idiopathic PD (IPD), as compared to control subjects [Kingsbury et al, 2001].…”

Perioperative Neuroprotection Symposium

“…Indeed, we found that the first window of IPC could not protect mitochondria against the deficits in respiration through complexes I -IV [55]. Rates of respiration in presence of pyruvate + malate and succinate + glycerol -3 -phosphate decreased in both the ischemia and in IPC groups marginally.…”

“…Lastly mitochondrial haplotypes in Caucasian patients (classified as haplotype J) markedly reduce the risk of developing PD [54]. The mRNA for the NDI subunit of mitochondrial complex I is reduced by 25% in the substantia nigra melanized neurons in PD [55].…”

“…However, protection only ensued if reperfusion was allowed to occur for 3 d but not beyond [47]. Thus, it was important to ascertain whether this lack of chronic protection was due to less protection against mitochondrial dysfunction by IPC.Indeed, we found that the first window of IPC could not protect mitochondria against the deficits in respiration through complexes I -IV [55]. Rates of respiration in presence of pyruvate + malate and succinate + glycerol -3 -phosphate decreased in both the ischemia and in IPC groups marginally.…”