DNA methylation increases during normal aging in many human tissues, including the brain (Chu et al., 2007
). Budovsky et al. (2006)
proposed that epigenetic changes in gene regulation are a central mechanism underlying aging and age-related pathologies. All genes listed as potential biomarkers of disease (, Column 3) are expressed in the cerebral cortex and are associated with neurological functioning. Siegmund et al. (2007)
reported that all of these genes are regulated by DNA methylation with progressively increased DNA methylation across the human lifespan. Therefore, abnormal methylation of these genes at younger ages could indicate accelerated aging and the early onset of neurological disease.
Studies in Mn-exposed rhesus monkeys identified changes in protein levels of two glutamate transporters (GLAST-1 and GLT-1) and tyrosine hydroxylase (TH), a key marker of dopaminergic neurons (Erikson et al., 2007
). The most significant decreases were in the globus pallidus, which is uniquely susceptible to Mn neurotoxicity. Although gene expression may be altered in humans as well, imaging techniques would appear to provide more useful data than a genetics-based approach.
More than a dozen genes have been linked to inherited forms of Parkinson’s Disease (PD), including PARK1 (α-synuclein), PARK2 (parkin), PARK6/PINK1, and PRK8/LRKK2 (reviewed in Gasser, 2007
; Deng et al., 2008
). Inheritance patterns include autosomal dominant, autosomal recessive, and X-linked inheritance (Chase, 1997
; Riess et al., 2002
; Warner and Schapira, 2003
; Gasser, 2007
). Genes associated with the development of Parkinson’s were not included in the candidate gene list, because PD pathology is different from manganese-induced toxicity although functional deficits may overlap. Magnetic resonance imaging clearly reveals Mn deposition and damage is greater in the globus pallidus compared with the substantia nigra which is most affected in PD (Shinotoh et al., 1995
; Kim, 2004
; Fitsanakis et al., 2008
). Patients suffering from Mn-induced neurotoxicity also do not respond to levodopa, the most common treatment for idiopathic PD (Lu et al., 1994
; Chu, 2004
; Koller et al., 2004
). Therefore, these genes were considered much weaker candidates for detailed genetic studies.
Only one research group has reported a direct link between genetic polymorphisms and the risk of parkinsonism in manganese-exposed workers. (Zheng et al., 2002
) reported that Chinese workers with a common polymorphism in CYP2D6 were at higher risk, although the authors concede the polymorphism they identified may only be a genetic marker with no direct physiological relevance to Mn neurotoxicity. Indeed, Dick et al. (2007a
) reported no association between CYP2D6 genotype and the development of parkinsonism in manganese-exposed workers studied in the European-based Geoparkinson study. The availability of a simple RFLP protocol to determine CYP2D6 genotype (Zheng et al., 2002
) provides a way to quickly screen large numbers of samples from the Marietta cohort, so we included this traditional technique in the pilot study. We also included CYP2D6 as a candidate gene because the putative susceptibility allele has a high prevalence in the human population.