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Parkinson disease: primacy of age as a risk factor for mitochondrial dysfunction.
Metabolism. 2008 Oct; 57 Suppl 2:S50-5.M

Abstract

In 1983, it was reported that certain drug users with a history of exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a contaminant of an illicitly produced meperidine analogue, developed an irreversible syndrome resembling idiopathic Parkinson disease (PD). Soon thereafter, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine's active metabolite, 1-methyl-4-phenylpyridine, was shown to be a complex I inhibitor. Activity of complex I (the point of entry for most electrons that traverse the mitochondrial electron transport chain) has been found to be impaired in the substantia nigra pars compacta and also in other brain tissues in PD patients. In 2006, high temporal and spatial resolution phosphorous functional magnetic resonance spectroscopy was used to demonstrate that, in 20 PD patients, mitochondrial dysfunction extended to the visual cortex. Epidemiologic studies have implicated a number of apparently disparate exogenous factors in the causation of PD. For example, exposure to certain pesticides and herbicides (many known to inhibit electron transport chain activity) increases PD risk. Parkinson disease risk can be doubled, tripled, or more in individuals with repeated head injuries. Over time, PD risk is almost doubled in men and women with prior type 2 diabetes mellitus. Nevertheless, despite evidence that certain exogenous and/or developmental factors play a role in causation of PD, their potential effect on PD incidence is greatly overshadowed by that of advancing age. In 1 prospective study, PD incidence rate in subjects at least 85 years old was about 14 times that observed in subjects aged 56 to 65 years. The dramatic effect of aging on PD risk may be explained in part by the fact that mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra pars compacta neurons. High levels of these mutations are associated with electron transport chain deficiency, a situation that favors increased oxidative damage, Lewy body formation, and apoptotic cell death. Systematic study of the effects of putative risk factors in animal models of parkinsonism may be expected to improve our understanding of PD's complex pathogenesis.

Authors+Show Affiliations

Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, St Luke's-Roosevelt Hospital Center, New York, NY 10025, USA. drvanitallie@comcast.net

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

18803967

Citation

Vanitallie, Theodore B.. "Parkinson Disease: Primacy of Age as a Risk Factor for Mitochondrial Dysfunction." Metabolism: Clinical and Experimental, vol. 57 Suppl 2, 2008, pp. S50-5.
Vanitallie TB. Parkinson disease: primacy of age as a risk factor for mitochondrial dysfunction. Metabolism. 2008;57 Suppl 2:S50-5.
Vanitallie, T. B. (2008). Parkinson disease: primacy of age as a risk factor for mitochondrial dysfunction. Metabolism: Clinical and Experimental, 57 Suppl 2, S50-5. https://doi.org/10.1016/j.metabol.2008.07.015
Vanitallie TB. Parkinson Disease: Primacy of Age as a Risk Factor for Mitochondrial Dysfunction. Metabolism. 2008;57 Suppl 2:S50-5. PubMed PMID: 18803967.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Parkinson disease: primacy of age as a risk factor for mitochondrial dysfunction. A1 - Vanitallie,Theodore B, PY - 2008/9/23/pubmed PY - 2008/10/16/medline PY - 2008/9/23/entrez SP - S50 EP - 5 JF - Metabolism: clinical and experimental JO - Metabolism VL - 57 Suppl 2 N2 - In 1983, it was reported that certain drug users with a history of exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a contaminant of an illicitly produced meperidine analogue, developed an irreversible syndrome resembling idiopathic Parkinson disease (PD). Soon thereafter, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine's active metabolite, 1-methyl-4-phenylpyridine, was shown to be a complex I inhibitor. Activity of complex I (the point of entry for most electrons that traverse the mitochondrial electron transport chain) has been found to be impaired in the substantia nigra pars compacta and also in other brain tissues in PD patients. In 2006, high temporal and spatial resolution phosphorous functional magnetic resonance spectroscopy was used to demonstrate that, in 20 PD patients, mitochondrial dysfunction extended to the visual cortex. Epidemiologic studies have implicated a number of apparently disparate exogenous factors in the causation of PD. For example, exposure to certain pesticides and herbicides (many known to inhibit electron transport chain activity) increases PD risk. Parkinson disease risk can be doubled, tripled, or more in individuals with repeated head injuries. Over time, PD risk is almost doubled in men and women with prior type 2 diabetes mellitus. Nevertheless, despite evidence that certain exogenous and/or developmental factors play a role in causation of PD, their potential effect on PD incidence is greatly overshadowed by that of advancing age. In 1 prospective study, PD incidence rate in subjects at least 85 years old was about 14 times that observed in subjects aged 56 to 65 years. The dramatic effect of aging on PD risk may be explained in part by the fact that mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra pars compacta neurons. High levels of these mutations are associated with electron transport chain deficiency, a situation that favors increased oxidative damage, Lewy body formation, and apoptotic cell death. Systematic study of the effects of putative risk factors in animal models of parkinsonism may be expected to improve our understanding of PD's complex pathogenesis. SN - 1532-8600 UR - https://www.unboundmedicine.com/medline/citation/18803967/Parkinson_disease:_primacy_of_age_as_a_risk_factor_for_mitochondrial_dysfunction_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0026-0495(08)00255-2 DB - PRIME DP - Unbound Medicine ER -