Ecogenetic theory

All About Parkinson's Disease

Parkinson Diseases Manual By Lianna Marie

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The ecogenetic theory of PD (see Fig. 1), adapted from the cancer literature and first

Fig. 1. The ecogenetic theory of PD

outlined by Barbeau and colleagues in their 1985 Lancet paper suggests that:

" ... Parkinson's disease is the result of environmental factors acting on genetically susceptible individuals against a background of normal ageing'' (Barbeau, 1985).

This statement, written 20 years ago remains totally consistent with all available current research evidence. Let's now briefly look at each aspect of this theory.

Environmental factors and PD

Intense interest in environmental exposures as risk factors for PD developed in the 1980s after reports confirmed that intoxication with the synthetic meperidine derivative, MPTP, could reproduce the features of PD in humans and animals. This stimulated a search for exogenous or endogenous molecules with similar effect. This also prompted a multitude of epidemiological surveys to assess potential environmental risk factors for Parkinson's disease. It is now clear that a number of classes of molecules have an ability to induce parkinsonism in animals and humans. Examples include the mitochondrial toxin rotenone, proteasomal pathway inhibitors and certain heavy metals. In addition, epidemiological surveys, mostly using a case-control experi mental design, have identified environmental exposures that may modify risk for the disease. Exposures to pesticides, neurotoxic metals, solvents, well water and rural residency reportedly increase risk; cigarette smoking and coffee consumption appear to be associated with a reduced risk. Despite considerable noise, three consistent findings emerge from such studies: (1) Exposure to pesticides is associated with increased risk; (2) Exposure to cigarette smoke is associated with a decreased risk; (3) A family history of PD is associated with increased risk.

These findings are consistent with the eco-genetic theory. Readers interested in further information about these risk factors are directed to meta-analyses that review the literature for these risk factors in more detail. Pesticide exposure yields a summary odds ratio (OR) of 1.94 (95%CI = 1.49-2.53) (Le Couteur et al., 1999). Smoking's effect is likewise modest (OR = 0.59, 95%CI = 0.54-0.63) (Hernan et al., 2002). These effect-sizes, which constitute a less than two-fold change in risk, require large sample sizes to detect.

With the caveat that family members tend to share environments and occupations, the family history story points to inherited factors (this will be discussed below).

Genetic factors and PD

That genes are important in the aetiology of PD is unequivocal. Rare monogenic forms of parkinsonism, resulting from genetic abnormalities in the so-called PARK genes are now well known. These are helping to define the important biological pathways leading to the neurodegeneration seen in PD. Twin studies, family studies and more complex genetic segregation analyses also point to a genetic component for typical idiopathic PD. It is, however, pertinent to remind the reader that the genetic component of PD is relatively modest. Moreover, the vast majority of individuals with PD have no apparent family history. Thus it is logical that any examination of genetic risk factors for PD should also consider their environmental context.

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