EDITORIAL
Parkmson’s Disease and
There is accumulating evidence that the pathogenesis of Parkinson’s disease (PD) may be related to both oxidative stress and a reduced ability to deal with oxidative stress. Endogenous factors include the metabolism of dopamine itself and conditions favoring oxidation in the substantia nigra. Several lines of evidence also suggest that the basal ganglia are particularly susceptible to abnormalities of the mitochondrial electron transport chain (ETC), the final common pathway for cellular energy metabolism. The ETC consists of 5 complexes that guide electrons to the final acceptor, oxygen, while adenosine triphosphate is generated, A role for dysfunction of the ETC in PD was suggested by the discovery that a metabolite of the neurotoxin l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP), which causes a parkinsonian syndrome, inhibits complex I in the ETC 111. After MPTP is metabolized to the active toxin MPP+ by MAO-B in glia, MPP’ is taken into dopaminergic neurons by the dopamine uptake pump, thus causing selective damage. Decreased complex I activity has been reported in both platelets of living PD patients 12} and postmortem brain of PD patients {3}. Parker and colleagues 121 found complex I activity to be 45% of control levels in 10 of 10 patients, suggesting that the complex I defect is present in an apparently unaffected tissue. Platelets have the advantage of not being subject to end-stage disease, neuronal dropout or postmortem artifact. Schapira and co-workers 131 found complex I activity to be 58% of control levels in postmortem substantia nigra, but not in a variety of other regions, including the caudate. They did not find any complex I abnormality in the substantia nigra of parkinsonian patients with multiple systems atrophy. Mizuno and colleagues [4] found decreases in the amount of 3 subunits of complex I by immunoblot in the striatum. There have been brief reports of functional deficits in complexes 11, I11 and IV 15-71. In this issue of the Amah, Shoffner and co-workers report abnormalities of the mitochondrial ETC in muscle biopsies of patients with PD. No abnormalities were found in the mitochondrial DNA. They found a complex I defect in 4 of 6 patients; a complex IV defect in 1 of 6 patients; variable findings in complexes I1 and 111 in 3 of 5 patients with complex I or IV defects; and no ETC defect in 1 of 6 patients. Given the heterogeneity of clinically diagnosed PD, it is not
surprising that 1 of 6 patients had no defect. The variable other ETC deficits, in addition to the complex I deficit, were not found in platelets or brain, but multiple ETC deficits are not uncommonly found in other mitochondrial cytopathies (see below). ETC defects have been observed in other neurodegenerative diseases. Parker and associates [S] reported finding a complex I defect in 5 of 5 Huntington’s disease patients, but no complex I defect was found in 5 subjects at risk. A complex IV defect was reported in 5 of 6 Alzheimer’s patients 191. Conversely, movement disorders are associated with toxin-induced or other genetic disturbances of the ETC. Poisoning with carbon monoxide and cyanide, both inhibitors of the ETC, produces sequelae including parkinsonism. The basal ganglia in general are affected grossly or functionally in known ETC disorders such as Leigh‘s disease, MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes), the variant of Leber’s disease associated with dystonia, and 9 of 85 patients with a variety of mitochondrial myopathies [lo]. The puzzling variety of clinical phenotypes that has been associated with functional defects of each of the ETC complexes may be due partly to tissue-specific isozymes or control mechanisms, but has yet to be fully explained. Notable in many of these other ETC disorders is the common occurrence of functional defects in several of the complexes of the ETC. These defects may be due to leakage of free radicals generated in the ETC, which would normally be tightly bound to the complexes. Liberation of these free radicals by a malfunctioning complex could lead to nonselective damage to nearby membranes, other components of the ETC, and mitochondrial DNA. Alrernatively, the underlying defect could fie in one of the nuclear-encoded proteins that direct or coordinate mitochondrial function, thus causing simultaneous dysfunction of one or more complexes. The facts that (1)Shoffner and colleagues found more ETC deficits in muscle than were found in platelets or brain, and (2) virtually aIl mitochondrial cytopathies-in which multiple defects commonly occur-are investigated in muscle biopsies, raise the question of whether muscle could be more sensitive to secondary effects of ETC defects than are other tissues. How then could a systemic biochemical disorder produce an apparently focal lesion? The answer may
330 Copyright 0 1991 by the American Neurological Association
lie partly with the special biochemical stresses placed on the dopaminergic neurons of the substantia nigra compacta (reviewed by Leehey and Boyson { 11)). These neurons are exposed to particularly high intracellular concentrations of dopamine, as the action of dopamine at the synapse is normally terminated by the reuptake of dopamine into these cells. The metabolism of dopamine and related compounds by monoamine oxidase (MAO) or by auto-oxidation in the presence of reduced iron or copper, results in the production of H,O,, which is metabolized to the hghly reactive hydroxyl free radical (.OH) in the presence of unbound, reduced iron. The *OH radical can be scavenged by glutathione peroxidase in the presence of reduced glutathione. The substantia nigra of patients with P D seems particularly vulnerable to these insults, having both increased iron content and decreased glutathione content. Products of lipid peroxidation, an indicator of free radical damage, have been found to be elevated in postmortem substantia nigra of PD patients. Preliminary results are encouraging from the DATATOP study {12), which is testing the hypothesis that selegiline (deprenyl), a selective MAO-B inhibitor, and/or vitamin E, a nonspecific “quencher” of free radicals-both designed to reduce oxidative stress in the substantia nigra-may retard progression of disease. The study of Shoffner and associates, which reports functional defects in the ETC in yet a third tissue (i.e., muscle, in addition to platelets and brain), places this finding on firmer ground and, together with the MPTP story, supports the hypothesis that a biochemical defect in the ETC may be instrumental in the pathogenesis of PD. Given the known low prevalence of familial PD, one might speculate that PD could be an autosomal dominant disorder that confers susceptibility, with very low penetrance due to factors that overload the impaired capacity of the substantia nigra to handle oxidative stress. The inconsistencies in ETC deficits other
than complex I, however, suggest that the full story has yet to unfold. Sally J. Boyson, MD Departments of Nezrrology and Pharmacology University of Colorado Health Sciences Center Denver, CO References 1. Nicklas WJ, Vyas I, Heikkila RE. Inhibition of NADH-linked oxidation in brain mitochondria by l-methyl-4-phenyl-pyridine, a metabolite of the neurotoxin, l-methyl-4-phenyi-l,2,5,6 tetrahydropyridine. Life Sci 1985;36:2503-2 508 2. Parker WD, Boyson SJ, Parks JK. Abnormalities of the electron transport chain in idiopathic Parkinson’s disease. Ann Neurol 1989;26:719-723 3. Schapira AHV, Mann VM, Cooper JM, et al. Anatomic and disease specificity of NADH C o Q l reductase (complex I) deficiency in Parkinson’s disease. J Neurochem 1990;55:2 1422145 4. Mizuno Y, Ohta S, Tanaka M, et al. Deficiencies in complex I subunits of the respiratory chain in Parkinson’s disease. Biochem Biophys Res Commun 1989;163:1450-1455 5. Mizuno Y, Suzuki K, Ohta S. Postmorten changes in mitochondrial respiratory enzymes in brain and a preliminary observation in Parkinson’s disease. J Neurol Sci 1990;96:49-57 6. Reichmann H, Riederer P, Seufert S, et al. Disturbances of the respiratory chain in brain from patients with Parkinson’s disease. Movr Dis 1990;5:28(Abstract) 7. Bindoff LA, Birch-Machin M, Cartlidge NEF, et al. Mitochondrial function in Parkinson’s disease. Lancet 1989;2:49 8. Parker WD, Boyson SJ, Luder AS, et al. Evidence for a defect in NADH. ubiquinone oxidoreductase (complex I) in Huntington’s disease. Neurology 1990;40:1231-1233 9. Parker WD, Filley CM, Parks JK. Cytochrome oxidase deficiency in Alzheimer’s disease. Neurology 1990;40:1302-1303 10. Truong DD, Harding AE, Scaravdh F, et al. Movement disorders in mirochondrial myoparhies. A study of nine cases with two autopsy studies. Movt Dis 1990;5:109-117 11. Leehey M, Boyson SJ. The biochemistry of Parkinson’s disease. In: Appel SH, ed. Current neurology, volume 11. St Louis: Mosby Year Book, 1991:233-286. 12. The Parkinson Study Group. Effect of deprenyl on the progression of disability in early Parkinson’s disease. N Engl J Med 198932 1:1364-1371
Editorial: Boyson: PD and the Electron Transport Chain
331
Parkmson’s Disease and
There is accumulating evidence that the pathogenesis of Parkinson’s disease (PD) may be related to both oxidative stress and a reduced ability to deal with oxidative stress. Endogenous factors include the metabolism of dopamine itself and conditions favoring oxidation in the substantia nigra. Several lines of evidence also suggest that the basal ganglia are particularly susceptible to abnormalities of the mitochondrial electron transport chain (ETC), the final common pathway for cellular energy metabolism. The ETC consists of 5 complexes that guide electrons to the final acceptor, oxygen, while adenosine triphosphate is generated, A role for dysfunction of the ETC in PD was suggested by the discovery that a metabolite of the neurotoxin l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP), which causes a parkinsonian syndrome, inhibits complex I in the ETC 111. After MPTP is metabolized to the active toxin MPP+ by MAO-B in glia, MPP’ is taken into dopaminergic neurons by the dopamine uptake pump, thus causing selective damage. Decreased complex I activity has been reported in both platelets of living PD patients 12} and postmortem brain of PD patients {3}. Parker and colleagues 121 found complex I activity to be 45% of control levels in 10 of 10 patients, suggesting that the complex I defect is present in an apparently unaffected tissue. Platelets have the advantage of not being subject to end-stage disease, neuronal dropout or postmortem artifact. Schapira and co-workers 131 found complex I activity to be 58% of control levels in postmortem substantia nigra, but not in a variety of other regions, including the caudate. They did not find any complex I abnormality in the substantia nigra of parkinsonian patients with multiple systems atrophy. Mizuno and colleagues [4] found decreases in the amount of 3 subunits of complex I by immunoblot in the striatum. There have been brief reports of functional deficits in complexes 11, I11 and IV 15-71. In this issue of the Amah, Shoffner and co-workers report abnormalities of the mitochondrial ETC in muscle biopsies of patients with PD. No abnormalities were found in the mitochondrial DNA. They found a complex I defect in 4 of 6 patients; a complex IV defect in 1 of 6 patients; variable findings in complexes I1 and 111 in 3 of 5 patients with complex I or IV defects; and no ETC defect in 1 of 6 patients. Given the heterogeneity of clinically diagnosed PD, it is not
surprising that 1 of 6 patients had no defect. The variable other ETC deficits, in addition to the complex I deficit, were not found in platelets or brain, but multiple ETC deficits are not uncommonly found in other mitochondrial cytopathies (see below). ETC defects have been observed in other neurodegenerative diseases. Parker and associates [S] reported finding a complex I defect in 5 of 5 Huntington’s disease patients, but no complex I defect was found in 5 subjects at risk. A complex IV defect was reported in 5 of 6 Alzheimer’s patients 191. Conversely, movement disorders are associated with toxin-induced or other genetic disturbances of the ETC. Poisoning with carbon monoxide and cyanide, both inhibitors of the ETC, produces sequelae including parkinsonism. The basal ganglia in general are affected grossly or functionally in known ETC disorders such as Leigh‘s disease, MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes), the variant of Leber’s disease associated with dystonia, and 9 of 85 patients with a variety of mitochondrial myopathies [lo]. The puzzling variety of clinical phenotypes that has been associated with functional defects of each of the ETC complexes may be due partly to tissue-specific isozymes or control mechanisms, but has yet to be fully explained. Notable in many of these other ETC disorders is the common occurrence of functional defects in several of the complexes of the ETC. These defects may be due to leakage of free radicals generated in the ETC, which would normally be tightly bound to the complexes. Liberation of these free radicals by a malfunctioning complex could lead to nonselective damage to nearby membranes, other components of the ETC, and mitochondrial DNA. Alrernatively, the underlying defect could fie in one of the nuclear-encoded proteins that direct or coordinate mitochondrial function, thus causing simultaneous dysfunction of one or more complexes. The facts that (1)Shoffner and colleagues found more ETC deficits in muscle than were found in platelets or brain, and (2) virtually aIl mitochondrial cytopathies-in which multiple defects commonly occur-are investigated in muscle biopsies, raise the question of whether muscle could be more sensitive to secondary effects of ETC defects than are other tissues. How then could a systemic biochemical disorder produce an apparently focal lesion? The answer may
330 Copyright 0 1991 by the American Neurological Association
lie partly with the special biochemical stresses placed on the dopaminergic neurons of the substantia nigra compacta (reviewed by Leehey and Boyson { 11)). These neurons are exposed to particularly high intracellular concentrations of dopamine, as the action of dopamine at the synapse is normally terminated by the reuptake of dopamine into these cells. The metabolism of dopamine and related compounds by monoamine oxidase (MAO) or by auto-oxidation in the presence of reduced iron or copper, results in the production of H,O,, which is metabolized to the hghly reactive hydroxyl free radical (.OH) in the presence of unbound, reduced iron. The *OH radical can be scavenged by glutathione peroxidase in the presence of reduced glutathione. The substantia nigra of patients with P D seems particularly vulnerable to these insults, having both increased iron content and decreased glutathione content. Products of lipid peroxidation, an indicator of free radical damage, have been found to be elevated in postmortem substantia nigra of PD patients. Preliminary results are encouraging from the DATATOP study {12), which is testing the hypothesis that selegiline (deprenyl), a selective MAO-B inhibitor, and/or vitamin E, a nonspecific “quencher” of free radicals-both designed to reduce oxidative stress in the substantia nigra-may retard progression of disease. The study of Shoffner and associates, which reports functional defects in the ETC in yet a third tissue (i.e., muscle, in addition to platelets and brain), places this finding on firmer ground and, together with the MPTP story, supports the hypothesis that a biochemical defect in the ETC may be instrumental in the pathogenesis of PD. Given the known low prevalence of familial PD, one might speculate that PD could be an autosomal dominant disorder that confers susceptibility, with very low penetrance due to factors that overload the impaired capacity of the substantia nigra to handle oxidative stress. The inconsistencies in ETC deficits other
than complex I, however, suggest that the full story has yet to unfold. Sally J. Boyson, MD Departments of Nezrrology and Pharmacology University of Colorado Health Sciences Center Denver, CO References 1. Nicklas WJ, Vyas I, Heikkila RE. Inhibition of NADH-linked oxidation in brain mitochondria by l-methyl-4-phenyl-pyridine, a metabolite of the neurotoxin, l-methyl-4-phenyi-l,2,5,6 tetrahydropyridine. Life Sci 1985;36:2503-2 508 2. Parker WD, Boyson SJ, Parks JK. Abnormalities of the electron transport chain in idiopathic Parkinson’s disease. Ann Neurol 1989;26:719-723 3. Schapira AHV, Mann VM, Cooper JM, et al. Anatomic and disease specificity of NADH C o Q l reductase (complex I) deficiency in Parkinson’s disease. J Neurochem 1990;55:2 1422145 4. Mizuno Y, Ohta S, Tanaka M, et al. Deficiencies in complex I subunits of the respiratory chain in Parkinson’s disease. Biochem Biophys Res Commun 1989;163:1450-1455 5. Mizuno Y, Suzuki K, Ohta S. Postmorten changes in mitochondrial respiratory enzymes in brain and a preliminary observation in Parkinson’s disease. J Neurol Sci 1990;96:49-57 6. Reichmann H, Riederer P, Seufert S, et al. Disturbances of the respiratory chain in brain from patients with Parkinson’s disease. Movr Dis 1990;5:28(Abstract) 7. Bindoff LA, Birch-Machin M, Cartlidge NEF, et al. Mitochondrial function in Parkinson’s disease. Lancet 1989;2:49 8. Parker WD, Boyson SJ, Luder AS, et al. Evidence for a defect in NADH. ubiquinone oxidoreductase (complex I) in Huntington’s disease. Neurology 1990;40:1231-1233 9. Parker WD, Filley CM, Parks JK. Cytochrome oxidase deficiency in Alzheimer’s disease. Neurology 1990;40:1302-1303 10. Truong DD, Harding AE, Scaravdh F, et al. Movement disorders in mirochondrial myoparhies. A study of nine cases with two autopsy studies. Movt Dis 1990;5:109-117 11. Leehey M, Boyson SJ. The biochemistry of Parkinson’s disease. In: Appel SH, ed. Current neurology, volume 11. St Louis: Mosby Year Book, 1991:233-286. 12. The Parkinson Study Group. Effect of deprenyl on the progression of disability in early Parkinson’s disease. N Engl J Med 198932 1:1364-1371
Editorial: Boyson: PD and the Electron Transport Chain
331
