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Toxins, genetics, and Parkinson's disease: the role of N-acetyltransferase 2
... Therefore, even though our results suggest the rapid acetylator phenotype increases risk for PSP, this is only one of potentially numerous factors that converge to determine individual risk for disease. On the other hand, our finding is contrary to recent findings that NAT2 rapid acetylator genes enhance the protective effect of smoking in PD (De Palma et al. 2010) and reports suggesting that the NAT2 slow acetylator phenotype increases risk for PD505152. PSP is a tauopathy and PD is a synucleinopathy, thus, these are two distinct diseases that may have distinct pathogenic mechanisms and risk factors [53]. There are varying reports of NAT2 polymorphisms associating with PD, PSP, and AD. ...
... There are varying reports of NAT2 polymorphisms associating with PD, PSP, and AD. While many suggest that slow alleles or phenotypes increase disease risk [31,32,505152, others indicate increased risk with rapid or intermediate conferring genotypes and protection by slow alleles or genotypes [13,54]. Still others suggest there are no links between In view of these conflicting reports on the role of NAT genetic polymorphisms in neurodegeneration together with our results, additional studies are needed to determine whether NAT alleles or genotypes conferring rapid acetylation increase risk for neurodegenerative diseases or if the slow alleles/genotypes are protective or vice versa. ...
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.
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.
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).
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.
... 46 The acetylator status may also influence gene expression and cell death in dopaminergic neurons. 47 Thus, the biological plausibility of the observed interaction may rely on the combination of the beneficial effects of tobacco smoke on dopaminergic transmission with better detoxification abilities and reduced cell death in smokers bearing NAT2 fast acetylator genotypes. ...
A case-control study of genetic, environmental, and occupational risk factors for Parkinson's disease (PD) was carried out in five European countries (Italy, Malta, Romania, Scotland, and Sweden) to explore the possible contribution of interactions among host and environmental factors in sporadic PD. Whereas smoking habits confirmed its negative association with PD, a possible modulatory role of genetic polymorphisms was investigated to obtain further mechanistic insights. We recruited 767 cases of PD and 1989 age-matched and gender-matched controls. Participants completed an interviewer-administered questionnaire including the history of smoking habits. The polymorphisms of genes involved either in metabolism of compounds contained in tobacco smoke (CYP2D6, CYP1B1, GSTM1, GSTT1, GSTM3, GSTP1, NQO1, SOD2, EPHX and NAT2) or in dopaminergic neurotransmission (MAOA, MAOB, DAT1 and DRD2) were characterized by PCR based methods on genomic DNA. We found evidence of statistically significant gene-tobacco interaction for GSTM1, NAT2, and GSTP1, the negative association between tobacco smoking and PD being significantly enhanced in subjects expressing GSTM1-1 activity, in NAT2 fast acetylators, and in those with the GSTP1*B*C haplotype. Owing to the retrospective design of the study, these results require confirmation.
... The identification of high levels of the M-D protein, -sarcoglycan, in DAergic neurons in the midbrain is notable in view of the evidence for altered DAergic transmission in other causes of dystonia. Levodopa-responsive dystonia is ameliorated by low levels of levodopa and is caused by reduced activity of GTP-I-cyclohydrolase, an enzyme needed for tetrahydrobiopterin production (Bandmann et al., 1999). Tetrahydrobiopterin is a cofactor for TH, the rate-limiting enzyme for DA synthesis (Robinson et al., 1999). ...
Myoclonus dystonia (M-D) is a hereditary movement disorder caused by a maternally imprinted gene that is often associated with psychiatric symptoms. Most cases of M-D are believed to result from mutations of the ϵ-sarcoglycan protein. The neuroanatomical distribution of ϵ-sarcoglycan-like immunoreactivity in mouse was investigated by using an antiserum against the ϵ-sarcoglycan protein. The expression of ϵ-sarcoglycan mRNA was studied by a sensitive fluorescence in situ hybridization (FISH) method. Immunohistochemistry and FISH revealed a wide distribution of ϵ-sarcoglycan protein and mRNA throughout the mouse brain. High expression levels of ϵ-sarcoglycan mRNA and immunoreactivity were found in the mitral cell layer of the olfactory bulb, the Purkinje cell layer in cerebellum, and the monoaminergic neurons in the mouse midbrain. Immunohistochemistry revealed a similar distribution of ϵ-sarcoglycan protein. Double-labeling FISH showed colocalization of tyrosine hydroxylase and ϵ-sarcoglycan mRNAs within all the midbrain dopaminergic (DAergic) cell groups. By combining FISH with fluorescence immunohistochemistry, coexpression of ϵ-sarcoglycan mRNA and tryptophan hydroxylase immunoreactivity was found in the serotonergic (5-HTergic) neurons within the dorsal raphe nucleus. The distribution of ϵ-sarcoglycan in the mouse brain suggests that the symptom complex of M-D may be related to the effects of decreased ϵ-sarcoglycan activity on the development or function of monoaminergic neurons. J. Comp. Neurol. 482:50–73, 2005. © 2004 Wiley-Liss, Inc.
... In addition, cancers of colon, breast, lung, head and neck, and prostate have been linked to NAT polymorphisms (Hein et al., 2000). Other disease states associated with NAT polymorphisms include Parkinson's disease (Bandmann et al., 1999; Agundez et al., 1998; Nicholl et al., 1999; Bandmann et al., 2000 ), isoniazid and rifampicininduced hepatotoxicity (Ohno et al., 2000), mild and severe substance abuse (Comings et al., 2000), periodontal disease (Meisel et al., 2000) and contact allergic diseases (Westphal et al., 2000; Gawronska-Szklarz et al., 1999). There are three NAT loci found on human chromosome 8 at 8p21.3 Á/23.1 (Hickman et al., 1994; Franke et al., 1994; Matas et al., 1997). ...
Arylamine N-acetyltransferase (NAT) enzymes catalyze the addition of an acetyl group from acetyl-CoA to a terminal nitrogen on a suitable substrate such as environmentally relevant compounds and pharmaceuticals. In human, there are two highly polymorphic active allozymes, NAT1 and -2, and one inactive pseudogene, NATP. The expression of these enzymes is tissue-specific such that NAT1 is ubiquitously expressed and NAT2 is confined mainly to liver and colorectal tissues. We hypothesized that these genes would be tissue-specifically transcriptionally regulated, and so we isolated putative proximal control regions for both the NAT genes, which were inserted into luciferase vectors and transiently transfected into human liver and bladder cells. The transfected cells were dosed with 4-aminosalicylic acid, sulfamethazine or solvent and the resulting luciferase activity was measured. We found that both NAT1 and -2 regions were inducible in liver cells by both xenobiotics but only one of the NAT1 regions was inducible again by both xenobiotics in bladder cells. These results suggest that the NAT genes may be tissue-specifically transcriptionally regulated.
Normal aging is a complex succession of physiological phenomenons leading to a gradual reduction of functional reserve in the entire organism. Illness rises when changes, accumulated along life, make impossible adaptation and homeostasis maintainance. A personal way of aging and the probability to ill and die in a particular time of life derive from interactions among genetics, environmental and psycho-social factors. With the latest technological-scientific progresses, a new methodology in medicine arises: the so-called "Predictive Medicine", capable to predict, prevent and/or slow the probable clinic history of everyone. Predictive Medicine, furthermore, might suggest new life-styles and/or individual therapy. In this contest, Geriatric Predictive Medicine could allow everyone to age healthy, without frailty and disability, by prevention and care of diseases such as Alzheimer's and Parkinson's diseases, cancer, metabolic syndrome, etc. A new very interesting and exciting field of research could be pharmaco-genomics. This science is looking for the best drug, the best posology patient-related. An excellent co-ordination among geriatricians in the Geriatric Services Net appears essential to allow a successful aging, without frailty and disability too. At last with the development of predictive medicine, important ethical questions for individual, family and society should be discussed and cleared up as soon as possible.
A case-control study of genetic, environmental, and occupational risk factors for Parkinson's disease (PD) was carried out in five European countries (Italy, Malta, Romania, Scotland, and Sweden) to explore the possible contribution of interactions among host and environmental factors in sporadic PD. Whereas smoking habits confirmed its negative association with PD, a possible modulatory role of genetic polymorphisms was investigated to obtain further mechanistic insights. We recruited 767 cases of PD and 1989 age-matched and gender-matched controls. Participants completed an interviewer-administered questionnaire including the history of smoking habits. The polymorphisms of genes involved either in metabolism of compounds contained in tobacco smoke (CYP2D6, CYP1B1, GSTM1, GSTT1, GSTM3, GSTP1, NQO1, SOD2, EPHX and NAT2) or in dopaminergic neurotransmission (MAOA, MAOB, DAT1 and DRD2) were characterized by PCR based methods on genomic DNA. We found evidence of statistically significant gene-tobacco interaction for GSTM1, NAT2, and GSTP1, the negative association between tobacco smoking and PD being significantly enhanced in subjects expressing GSTM1-1 activity, in NAT2 fast acetylators, and in those with the GSTP1*B*C haplotype. Owing to the retrospective design of the study, these results require confirmation.
Many toxicological and epidemiological studies have shown that acetyltransferases play a crucial role in the metabolism of potential carcinogenic aromatic amines and nitroarenes. They may therefore be of central importance for the induction of tumors by these substances. Human N-acetyltransferase enzymes exist in two forms which can be distinguished by their high specificity for the substrates p-aminobenzoic acid (PABA, for NAT1) and isoniacid (INH, for NAT2). Actual knowledge about presence and activity of these enzymes in human tissues is unsure and incomplete. One of the reasons for this is the high instability which was not considered adequately in previous studies. Another reason has been the low specificity and sensitivity of the methods used for the determination of NAT activity in the past. The present study aimed at determining the activity of the two NATs in lung, intestine, tissues of the urogenital tract and skin with methods avoiding the errors made in the past. Therefore, only freshly collected specimen were used and activities of NAT were determined using PABA and INH as substances in a HPLC-based approach. Prior studies have shown, that activities were stable for about 10 hours at +4° C, in contrast to storing the tissues at either -80° C or -180° C which led to strong losses in activity. Under the conditions used significant activities of NAT1 (PABA) could be found in all samples of skin (n=8), kidney (n=5), ureter (n=5), urinary bladder (n=4), prostate (n=2), liver (n=2), pancreas (n=2), small intestine (n=1), colon (n=5), rectum (n=4) and lung (n=7). In most of the tissues these activities showed to be in the order of 1.5 -3 nmol/mg/min. Activities of intestinal tissues were clearly higher with levels of about 8 nmol/mg/min, those in pancreas with about 0.5 - 1 nmol/mg/min somewhat lower than those observed in the other tissues. However, only a few tissues showed significant activities of NAT2 (INH). Activities were about 100 - 300 pmol/mg/min in specimen of liver and intestine and only 50 pmol/mg/min in the lung. Interindividual variation coefficients were of the same magnitude for NAT1 (ca. 50%) and NAT2 (ca. 40%) in all tissues. Compared with commonly used animal models mice, rats and hamsters showed bigger differences to conditions found in humans, whereas the rabbit seems to resemble most.
Agents potentially involved in the aetiology of idiopathic Parkinson's disease are discussed. These include factors regulating dopaminergic neurogenesis (Nurr 1, Ptx-3, and Lmx1b) and related proteins, together with genes involved in familial Parkinson's disease (alpha synuclein, parkin, and ubiquitin carboxy terminal hydroxylase L1), and endogenous and environmental agents.
The role of N-acetyltransferase gene (NAT2) polymorphism in the aetiology of Alzheimer's disease (AD) and Parkinson's disease (PD) is an interesting issue; it is suggested that the slow acetylator genotype favours the damage of central nervous system cells by environmental toxins. The aims of the study were: 1) to determine the genotype of NAT2 in patients with sporadic PD with dementia and in patients with sporadic AD; 2) to evaluate the relationship between the genotype of NAT2 and the age at the onset of the disease, the extent of dementia, and the dose and side effects of L-dopa (in PD patients only); 3) to evaluate the predispositions to PD and AD.
Fifty two PD patients with dementia aged 51-82 years (mean: 70.35) and 53 AD patients aged 58-84 years (mean: 72.58) were recruited. The control group consisted of 90 healthy subjects aged 65-86 years (mean: 72.11). Four standardized instruments for evaluation of dementia in PD patients were used. Clinical scales for PD evaluation were used. Each AD patient satisfied the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association criteria for probable AD. Methods of molecular biology were used for genetic studies.
The NAT2*5/NAT2*5 genotype was more frequent in PD patients with dementia; the NAT2*4/NAT2*5 genotype was more frequent and the NAT2*4/NAT2*6 genotype was less frequent in AD patients. No relationship was found between genotypes and NAT2 alleles and the age at onset, severity of dementia or with the dose and side effects of L-dopa (in PD patients).
The analysis of NAT2 polymorphism does not seem to be useful in predicting the risk of PD with dementia or AD.
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