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