Peter Jenner

Mitochondrial Complex I Deficiency in Parkinson's Disease

Abstract: The structure and function of mitochondrial respiratory‐chain enzyme proteins were studied postmortem in the substantia nigra of nine patients with Parkinsons disease and nine matched controls. Total protein and mitochondrial mass were similar in the two groups. NADH‐ubiquinone reductase (Complex I) and NADH cytochrome c reductase activities were significantly reduced, whereas succinate cytochrome c reductase activity was normal. These results indicated a specific defect of Complex I activity in the substantia nigra of patients with Parkinsons disease. This biochemical defect is the same as that produced in animal models of parkinsonism by 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) and adds further support to the proposition that Parkinsons disease may be due to an environmental toxin with action(s) similar to those of MPTP.

Oxidative stress in Parkinson's disease

Oxidative stress contributes to the cascade leading to dopamine cell degeneration in Parkinsons disease (PD). However, oxidative stress is intimately linked to other components of the degenerative process, such as mitochondrial dysfunction, excitotoxicity, nitric oxide toxicity and inflammation. It is therefore difficult to determine whether oxidative stress leads to, or is a consequence of, these events. Oxidative damage to lipids, proteins, and DNA occurs in PD, and toxic products of oxidative damage, such as 4‐hydroxynonenal (HNE), can react with proteins to impair cell viability. There is convincing evidence for the involvement of nitric oxide that reacts with superoxide to produce peroxynitrite and ultimately hydroxyl radical production. Recently, altered ubiquitination and degradation of proteins have been implicated as key to dopaminergic cell death in PD. Oxidative stress can impair these processes directly, and products of oxidative damage, such as HNE, can damage the 26S proteasome. Furthermore, impairment of proteasomal function leads to free radical generation and oxidative stress. Oxidative stress occurs in idiopathic PD and products of oxidative damage interfere with cellular function, but these form only part of a cascade, and it is not possible to separate them from other events involved in dopaminergic cell death. Ann Neurol 2003;53 (suppl 3):S26–S38

Basal Lipid Peroxidation in Substantia Nigra Is Increased in Parkinson's Disease

Abstract: Polyunsaturated fatty acid (PUFA) levels (an index of the amount of substrate available for lipid peroxidation) were measured in several brain regions from patients who died with Parkinsons disease and age‐matched control human postmortem brains. PUFA levels were reduced in parkinsonian substantia nigra compared to other brain regions and to control tissue. However, basal malondialdehyde (MDA; an intermediate in the lipid peroxidation process) levels were increased in parkinsonian nigra compared with other parkinsonian brain regions and control tissue. Expressing basal MDA levels in terms of PUFA content, the difference between parkinsonian and control substantia nigra was even more pronounced. Stimulating MDA production by incubating tissue with FeSO4 plus ascorbic acid, FeSO4 plus H2O2, or air alone produced lower MDA levels in the parkinsonian substantia nigra, probably reflecting the lower PUFA content. These results may indicate that an increased level of lipid peroxidation continues to occur in the parkinsonian nigra up to the time of death, perhaps because of continued exposure to excess free radicals derived from some endogenous or exogenous neurotoxic species.

Mitochondrial complex I deficiency in Parkinson's disease.

The structure and function of mitochondrial respiratory-chain enzyme proteins were studied postmortem in the substantia nigra of nine patients with Parkinsons disease and nine matched controls. Total protein and mitochondrial mass were similar in the two groups. NADH-ubiquinone reductase (Complex I) and NADH cytochrome c reductase activities were significantly reduced, whereas succinate cytochrome c reductase activity was normal. These results indicated a specific defect of Complex I activity in the substantia nigra of patients with Parkinsons disease. This biochemical defect is the same as that produced in animal models of parkinsonism by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and adds further support to the proposition that Parkinsons disease may be due to an environmental toxin with action(s) similar to those of MPTP.

Increased Nigral Iron Content and Alterations in Other Metal Ions Occurring in Brain in Parkinson's Disease

Abstract: Levels of iron, copper, zinc, manganese, and lead were measured by inductively coupled plasma spectroscopy in parkinsonian and age‐matched control brain tissue. There was 31‐35% increase in the total iron content of the parkinsonian substantia nigra when compared to control tissue. In contrast, in the globus pallidus total iron levels were decreased by 29% in Parkinsons disease. There was no change in the total iron levels in any other region of the parkinsonian brain. Total copper levels were reduced by 34–45% in the substantia nigra in Parkinsons disease; no difference was found in the other brain areas examined. Zinc levels were increased in substantia nigra in Parkinsons disease by 50–54%, and the zinc content of the caudate nucleus and lateral putamen was also raised by 18–35%. Levels of manganese and lead were unchanged in all areas of the parkinsonian brain studied when compared to control brains, except for a small decrease (20%) in manganese content of the medial putamen. Increased levels of total iron in the substantia nigra may cause the excessive formation of toxic oxygen radicals, leading to dopamine cell death.

Oxidative stress and the pathogenesis of Parkinson's disease

Current concepts of the pathogenesis of Parkinsons disease (PD) center on the formation of reactive oxygen species and the onset of oxidative stress leading to oxidative damage to substantia nigra pars compacta.Extensive postmortem studies have provided evidence to support the involvement of oxidative stress in the pathogenesis of PD; in particular, these include alterations in brain iron content, impaired mitochondrial function, alterations in the antioxidant protective systems (most notably superoxide dismutase [SOD] and reduced glutathione [GSH]), and evidence of oxidative damage to lipids, proteins, and DNA. Iron can induce oxidative stress, and intranigral injections have been shown to induce a model of progressive parkinsonism. A loss of GSH is associated with incidental Lewy body disease and may represent the earliest biochemical marker of nigral cell loss. GSH depletion alone may not result in damage to nigral neurons but may increase susceptibility to subsequent toxic or free radical exposure. The nature of the free radical species responsible for cell death in PD remains unknown, but there is evidence of involvement of hydroxyl radical (OH sup [bullet]), peroxynitrite, and nitric oxide. Indeed, OH sup [bullet] and peroxynitrite formation may be critically dependent on nitric oxide formation. Central to many of the processes involved in oxidative stress and oxidative damage in PD are the actions of monoamine oxidase-B (MAO-B). MAO-B is essential for the activation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine to 1-methyl-4-phenylpyridinium ion, for a component of the enzymatic conversion of dopamine to hydrogen peroxide (H2 O2), and for the activation of other potential toxins such as isoquinolines and beta-carbolines. Thus, the inhibition of MAO-B by drugs such as selegiline may protect against activation of some toxins and free radicals formed from the MAO-B oxidation of dopamine. In addition, selegiline may act through a mechanism unrelated to MAO-B to increase neurotrophic factor activity and upregulate molecules such as glutathione, SOD, catalase, and BCL-2 protein, which protect against oxidant stress and apoptosis. Consequently, selegiline may be advantageous in the long-term treatment of PD. NEUROLOGY 1996;47(Suppl 3): S161-S170

Oxidative DNA damage in the Parkinsonian brain : An apparent selective increase in 8-hydroxyguanine levels in substantia nigra

Abstract: Oxidative damage has been implicated in the pathology of Parkinsons disease (PD), e.g., rises in the level of the DNA damage product, 8‐hydroxy‐2′‐deoxyguanosine, have been reported. However, many other products result from oxidative DNA damage, and the pattern of products can be diagnostic of the oxidizing species. Gas chromatography/mass spectrometry was used to examine products of oxidation and deamination of all four DNA bases in control and PD brains. Products were detected in all brain regions examined, both normal and PD. Analysis showed that levels of 8‐hydroxyguanine (8‐OHG) tended to be elevated and levels of 2,6‐diamino‐4‐hydroxy‐5‐formamidopyrimidine (FAPy guanine) tended to be decreased in PD. The most striking difference was a rise in 8‐OHG in PD substantia nigra (p = 0.0002); rises in other base oxidation/deamination products were not evident, showing that elevation in 8‐OHG is unlikely to be due to peroxynitrite (ONOO−) or hydroxyl radicals (OH•), or to be a prooxidant effect of treatment with l‐Dopa. However, some or all of the rise in 8‐OHG could be due to a change in 8‐OHG/FAPy guanine ratios rather than to an increase in total oxidative guanine damage.

Anatomic and Disease Specificity of NADH CoQ1 Reductase (Complex I) Deficiency in Parkinson's Disease

Abstract: 1‐Methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) is thought to produce parkinsonism in humans and other primates through its inhibition of complex I. The recent discovery of mitochondrial complex I deficiency in the substantia nigra of patients with Parkinsons disease has provided a remarkable link between the idiopathic disease and the action of the neurotoxin MPTP. This article shows that complex I deficiency in Parkinsons disease is anatomically specific for the substantia nigra, and is not present in another neurodegenerative disorder involving the substantia nigra. Evidence is also provided to show that there is no correlation between l‐3,4‐dihydroxyphenylalanine therapy and complex I deficiency. These results suggest that complex I deficiency may be the underlying cause of dopaminergic cell death in Parkinsons disease.

Proteasomal function is impaired in substantia nigra in Parkinson's disease

The accumulation of alpha-synuclein, ubiquitin and other proteins in Lewy bodies in degenerating dopaminergic neurones in substantia nigra in idiopathic Parkinsons disease (PD) suggest that inhibition of normal/abnormal protein degradation may contribute to neuronal death. We now show for the first time that the chymotrypsin- (39%), trypsin- (42%) and postacidic-like (33%) hydrolysing activities of 20/26S proteasome are impaired in substantia nigra in PD. Proteasome inhibition does not appear to result from drug treatment since high concentrations of L-3,4-dihydroxyphenylalanine had no effect on enzymatic activity in vitro. These observations provide the first direct evidence that inhibition of the ubiquitin-proteasome pathway leading to altered protein handling and Lewy body formation may be responsible for degeneration of the nigrostriatal pathway in idiopathic PD.

Altered Proteasomal Function in Sporadic Parkinson's Disease

Parkinsons disease (PD) is characterized pathologically by preferential degeneration of the dopaminergic neurons in the substantia nigra pars compacta (SNc). Nigral cell death is accompanied by the accumulation of a wide range of poorly degraded proteins and the formation of proteinaceous inclusions (Lewy bodies) in dopaminergic neurons. Mutations in the genes encoding alpha-synuclein and two enzymes of the ubiquitin-proteasome system, parkin and ubiquitin C-terminal hydrolase L1, are associated with neurodegeneration in some familial forms of PD. We now show that, in comparison to age-matched controls, alpha-subunits (but not beta-subunits) of 26/20S proteasomes are lost within dopaminergic neurons and 20S proteasomal enzymatic activities are impaired in the SNc in sporadic PD. In addition, while the levels of the PA700 proteasome activator are reduced in the SNc in PD, PA700 expression is increased in other brain regions such as the frontal cortex and striatum. We also found that levels of the PA28 proteasome activator are very low to almost undetectable in the SNc compared to other brain areas in both normal and PD subjects. These findings suggest that failure of the ubiquitin-proteasome system to adequately clear unwanted proteins may underlie vulnerability and degeneration of the SNc in both sporadic and familial PD.