Polymorphic genes of detoxification and mitochondrial enzymes and risk for progressive supranuclear palsy: a case control study

Lisa F Potts 0 Alex C Cambon 2 Owen A Ross 1 Rosa Rademakers 1 Dennis W Dickson 1 Ryan J Uitti 6 Zbigniew K Wszolek 6 Shesh N Rai 2 5 Matthew J Farrer 1 4 David W Hein 3 5 Irene Litvan 0 7 8 0 Department of Anatomical Sciences and Neurobiology, University of Louisville , Louisville, KY , USA 1 Department of Neuroscience, Mayo Clinic Jacksonville , Jacksonville, FL , USA 2 Department of Bioinformatics and Biostatistics, University of Louisville , Louisville, KY , USA 3 Department of Pharmacology and Toxicology, University of Louisville , Louisville, KY , USA 4 Department of Medical Genetics, Centre of Applied Neurogenetics, Brain Research Centre, University of British Columbia , Vancouver, British Columbia , Canada 5 J.G. Brown Cancer Center, University of Louisville , Louisville, KY , USA 6 Department of Neurology, Mayo Clinic Jacksonville , Jacksonville, FL , USA 7 Department of Neurosciences, University of California San Diego , La Jolla, CA , USA 8 Department of Neurology, University of Louisville , Louisville, KY , USA Background: There are no known causes for progressive supranuclear palsy (PSP). The microtubule associated protein tau (MAPT) H1 haplotype is the major genetic factor associated with risk of PSP, with both oxidative stress and mitochondrial dysfunction also implicated. We investigated whether specific single nucleotide polymorphisms (SNPs) in genes encoding enzymes of xenobiotic detoxification, mitochondrial functioning, or oxidative stress response, including debrisoquine 4-hydroxylase, paraoxonase 1 and 2, N-acetyltransferase 1 and 2 (NAT2), superoxide dismutase 1 and 2, and PTEN-induced putative kinase are associated with PSP. Methods: DNA from 553 autopsy-confirmed Caucasian PSP cases (266 females, 279 males; age at onset 68 8 years; age at death 75 8) from the Society for PSP Brain Bank and 425 clinical control samples (197 females, 226 males; age at draw 72 11 years) from healthy volunteers were genotyped using Taqman PCR and the SequenomiPLEX Gold assay. Results: The proportion of NAT2 rapid acetylators compared to intermediate and slow acetylators was larger in cases than in controls (OR = 1.82, p < 0.05). There were no allelic or genotypic associations with PSP for any other SNPs tested with the exception of MAPT (p < 0.001). Conclusions: Our results show that NAT2 rapid acetylator phenotype is associated with PSP, suggesting that NAT2 may be responsible for activation of a xenobiotic whose metabolite is neurotoxic. Although our results need to be further confirmed in an independent sample, NAT2 acetylation status should be considered in future genetic and epidemiological studies of PSP. - Background Progressive supranuclear palsy (PSP) is the most common atypical parkinsonian disorder. Classically, patients present with progressive postural instability and falls followed by slow and hypometric vertical saccades and eventually vertical supranuclear gaze palsy. Neuropathologically, PSP is characterized by deposits of four-repeat microtubule associated protein tau (encoded by the MAPT gene) aggregates in neurons and glia of the basal ganglia and brain-stem [1]. Additionally, there is mitochondrial dysfunction, decreased ATP levels and inflammation in the brains of PSP patients [2-4]. The MAPT H1 haplotype has been consistently reported to be associated with PSP; however, it is also common in the general population, suggesting that gene-gene or gene-environment interactions are likely required for the development of this disease [5,6]. Recently, MAPT H1 was also associated with risk of Parkinsons disease (PD) suggesting shared pathways of disease [7]. Earlyonset PD and PSP can present with a similar phenotype and be misdiagnosed, supporting common links between the two disorders. The product of PTEN-induced putative kinase (PINK1, PARK6), associated with earlyonset PD, is involved in mitochondrial respiration and protection from oxidative damage, which are pathways that have also been linked to risk of PSP [8-13]. PINK-1 polymorphisms are also associated with PD and it acts in conjunction with parkin to regulate mitochondrial functioning. Although the mechanisms by which PINK1 acts are not fully understood; research suggests that it is crucial for healthy mitochondrial respiration and ATP production [8]. Considering the role of PINK1 in mitochondrial functioning along with its previous links to PD, specific PINK1 SNPs were included in this study to determine if there is also an association with PSP. Consumption of annonaceous fruit and teas, which contain mitochondrial inhibitors, has been associated with an atypical parkinsonian disorder similar to PSP in the French West Indies [14,15]. Considering that mitochondrial impairment is observed in PSP brains, mitochondrial complex-1 inhibitors and other chemical neurotoxins, such as organophosphates, are hypothesized as risk factors for PSP [16-18]. These and other potentially toxic compounds are metabolized by the products of several genes: debrisoquine 4-hydroxylase (CYP2D6), paraoxonase (PON) 1 and 2, N-acetyltransferase (NAT) 1 and 2, and superoxide dismutase (SOD) 1 and 2 [10-13,19-22]. CYP2D6 is found in the brain and is involved in metabolism of MPTP, herbicides (paraquat) and organophosphate pesticides [11,12]. Reduced in 5-10% of Caucasians, genetic polymorphisms of this enzyme have been widely studied in PD and results suggest that there is an association of the poor metabolizer phenotype with disease development [23,24]. Moreover, the combination of pesticide exposure and CYP2D6 poor metabolizer phenotype doubles PD risk [11,20]. PON1 hydrolyzes phosphoric acid esters, organophosphates and aromatic carboxylic acid esters and blocks the formation of free radicals. With low PON1 activity, these pesticides are not metabolized and the cell is subject to increased oxidative stress [19]. The PON 1 M allele, which is correlated with decreased protein levels, has been shown to be associated with PD [25,26] and the M/M genotype was recently reported to be associated with early onset PD [27]. Additionally, decreased PON1 activity was overrepresented in PD patients from agriculturally exposed areas [19]. NAT1 and NAT2 are involved in the biotransformation of drugs and environmental toxins (xenobiotics) [28]. These enzymes transfer the acetyl group from acetyl-coenzyme A (acetyl CoA) to an amino group on aromatic amines and hydrazine compounds. In addition, following N-hydroxylation, they can further activate xenobiotics via O-acetylation [29]. There are a number of SNPs reported in NAT1 and NAT2, which lead to slow and rapid acetylator phenotypes. The acetylation status of an individual might determine how they respond to xenobiotic exposures, therefore presenting the NAT genes as candidates for gene-environment interaction studies. The slow acetylator phenotype is reported to be associated with PD, but inconsistent results warrant further investigation [30-34]. SOD is an important ant (...truncated)