Brain, Skeletal Muscle and Platelet Homogenate Mitochondrial Function in Parkinson's Disease

Abstract

The recent discovery of mitochondrial complex I deficiency in the substantia nigra of patients with idiopathic Parkinson's disease has provided new understanding into the possible mechanisms that may underlie this neurodegenerative disorder. The biochemical defect is identical to that induced in humans, primates and mice exposed to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. We have studied mitochondrial respiratory chain function in various brain regions, in skeletal muscle and in blood platelets from patients with idiopathic Parkinson's disease and from matched controls. We provide evidence suggesting that the complex I deficiency in Parkinson's disease is limited to the brain and that this defect is specific for the substantia nigra. The tissue specificity of the complex I deficiency in Parkinson's disease and its localization to the substantia nigra support the proposition that complex I deficiency may be directly involved in the cause of dopaminergic cell death in Parkinson's disease. An understanding of the molecular basis of this biochemical defect will provide valuable insight into the cause of Parkinson's disease. Our findings of normal mitochondrial function in platelet homogenates suggests that this tissue cannot be used to develop a 'diagnostic test' for Parkinson's disease.

Neuronal complex I deficiency occurs throughout the Parkinson’s disease brain, but is not associated with neurodegeneration or mitochondrial DNA damage

“…Our findings appear to contradict studies showing normal complex I activity in homogenized tissue of the cerebellum, striatum [18,24,25,36] and frontal cortex [18,36] in PD. This difference may be partly due to lower sensitivity of analyses in brain homogenate.…”

“…Subsequently, evidence of complex I deficiency was shown in the SNc of individuals with idiopathic PD [25,35]. While this phenomenon has been consistently reproduced by multiple studies [17,18,23,24,34] its significance remains undetermined. It is unclear whether complex I deficiency in PD is a primary pathogenic event compromising neuronal integrity, an adaptive response to disease-related stress, or merely a symptom of end-stage dysfunction in terminally ill neurons.…”

“…One recent study found that complex I activity was decreased in prefrontal cortex homogenate from individuals with Parkinson's disease dementia (PDD), but within normal range in non-demented PD individuals [14]. Complex I activity measurements and/or Western blot quantification in homogenized samples of the cerebellum and striatum have shown normal findings [18,24,25,36]. Other brain areas remain unexplored.…”

Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease—resemblance to the effect of amphetamine drugs of abuse

“…Complex I activity and expression are decreased in the SN[109Ͳ112] and cortex [113] of PD patients to a greater extent than would be expected from normal aging [107]. Oxidized, functionally impaired and misassembled complex I subunits, have been reported in PD [114].Moreover, complex I dysfunction was reported in skeletal muscle and platelets of PD patients [112].…”

Reprint of: Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease—resemblance to the effect of amphetamine drugs of abuse

“…Oxidized, functionally impaired, and misassembled complex I subunits have been reported in PD [114]. Moreover, complex I dysfunction was reported in skeletal muscle and platelets of PD patients [112].…”