Environment, Genetics and Idiopathic Parkinson's Disease

Abstract

ABSTRACT:Since Idiopathic Parkinson's disease (IPD) was first described more than 170 years ago, there have been major advances in the understanding of the etiology of the disease as well as in its treatment. This article will review current knowledge concerning the role of the environment, genetic hypotheses and the aging factor in the etiology of IPD and proposes a complex interaction involving all these factors. Hypotheses regarding mitochondrial inhibition and free radical generation in IPD are discussed in relation to the mechanism of action of neurotoxins known to produce parkinsonian syndromes. RESUME: Depuis sa description initiale il y a un peu plus de 170 ans, de nombreuses decouvertes fondamentales et cliniques ont permis de mieux compredre la maladie de Parkinson. Cet article detaille certaines observations recentes concernant le role possible de l'environnement, la genetique et le vieillissement dans I'etiologie de la maladie de Parkinson. Les hypotheses concernant l'inhibition mitochondriale et la generation de radicaux libres dans la maladie de Parkinson sont discutees en rapport avec les mecanismes d'action de neurotoxines connues comme produisant des syndromes parkinsoniens.Can. J. Neurol. Sci. 1991; 18: 70-76 Idiopathic Parkinson's disease (IPD) is characterized by major clinical disturbances caused by dopamine depletion in the corpus striatum, resulting from neuronal loss in the substantia nigra (SN).1 The dopamine depletion is the result of a severe degeneration of the dopaminergic nigro-striatal pathway which normally inhibits the activity of a subpopulation of striatal neurons. While the physiological and neurochemical consequences of the dopamine depletion have been extensively documented, very little is known about the underlying cause of dopamine cell death or the mechanism by which dopamine cells degenerate. Numerous hypotheses have been presented including the following: a) IPD is the result of a random process.2 This hypothesis assumes that the age-related loss of neurons can be accelerated by the cumulative action of repeated insults of ordinary life (viruses, toxins, head injury, etc.). A revised form of this concept is also known as the "accelerated aging hypothesis". 3 b) IPD is the result of a lack of neurotrophic hormone. 4 It is hypothesized that a dopaminergic-specific growth factor is synthesized and stored in the target striatal cells and that the inability of these cells to provide the required dopaminergic neurotrophic hormone, thereby causes impairment to SN neurons, c) IPD is caused by a defect in the DNA repair mechanism.5 This hypothesis is derived from observations showing that cultured fibroblasts from parkinsonian patients are hypersensitive to the lethal effects of DNA-damaging agents such as x-rays. It postulates that somatic mutations occurring in early embryogenesis cause a lifelong accumulation of unrepaired DNA damage in neurons, resulting in lethal consequences on the SN. d) IPD is the result of a specific genetic defect(s) or genetic predisposition(s).3 '...

Stimulation of the rat subthalamic nucleus is neuroprotective following significant nigral dopamine neuron loss

“…We appreciate that the intrastriatal 6-OHDA model is not PD however the exact cause of DA neuron degeneration in sporadic PD is currently unknown. Decades of research have indicated that the disease is likely due to cumulative effects of genetic and environmental factors (Elbaz, et al 2007, Migliore and Coppede 2009, Mouradian 2002, Poirier, et al 1991). Oxidative stress has been consistently implicated in contributing to the pathology of PD (Henchcliffe and Beal 2008, Jenner 2007, Przedborski, et al 2001).…”

Temporal mRNA profiles of inflammatory mediators in the murine 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrimidine model of Parkinson’s disease

“…The etiology of PD is thought to involve interplay between environmental agents and genetic risk factors (Poirier et al, 1991,Tsang and Soong, 2003,Allam et al, 2005. A number of inbred strains of mice with differential sensitivity to MPTP have been identified and can be used to identify genetic factors (Hamre et al, 1999,Schwarting et al, 1999,Smeyne et al, 2001,Cook et al, 2003,Liu et al, 2003a,McLaughlin et al, 2006.…”

Parkinson's Disease Mortality in Italy, 1951 Through 1987

“…Many possible causative factors have been suggest¬ ed, including environmental toxic agents,1 abiotrophy and aging,2 lack of neurotropic hormones,3 genetic defects or genetic predisposition,4 defect of DNA repair mechanism,5 and viral infections.6-7 None of these hypotheses fully ex¬ plains the events responsible for the initiation of PD or identifies its cause. 8 Despite the diffusion of the disease and its impact on public health, comparatively little interest has been direct¬ ed to its epidemiology. Epidemiologie surveys seem to in¬ dicate that PD is less common among nonwhites910 and that the disease is unevenly distributed in Western coun¬ tries.1112 A decreasing north-to-south gradient in mortality has been observed in the United States.10 Annual mortal¬ ity in 33 European and American countries in 1951 through 1958 was between 0.5 and 3.8/100 000.13 An increase in mortality in patients older than 75 years and a decrease in rates in younger subjects has been observed in the United States during the last two decades1415 and also in some Eu¬ ropean countries.16…”