**4. Polymorphisms of** *MTHFR, MTR, MTHFD1* **and the level of biothiols in Parkinson's disease**

The enzyme MTHFR plays a key role in regulating of Hcy metabolism. The study of Yasui et al. (2000) indicated that the TT *MTHFR* C677T genotype might also be linked to pathogenesis of PD, particularly when the level of folates is low. However, Fong et al. (2011) indicated on synergistic effects of polymorphisms in the folate metabolic pathway genes in PD not only C677T *MTHFR*, but also A2756G of *MTR* and A1049G, C1783T of *MTRR* (methionine synthase reductase). Yuan et al. (2009) showed on synergism between Hcy elevation after L-dopa administration in PD patients and *MTHFR,* CT and TT (C677T) genotypes. The study of Dorszewska et al. (2007) indicated that the genotypes TT (C677T), CC (A1298C) and AA (G1793A) of *MTHFR* have been the least frequent in patients with neurodegenerative disorders and their incidence has been slightly increased in the degenerative diseases (e.g. PD). In study of Dorszewska et al. (2007) also indicated that in PD patients Hcy has reached higher levels only in patients with CT genotype of *MTHFR* C677T. It seems that, particularly in persons with CT genotype of the C677T polymorphism of *MTHFR*, processes of Hcy transsulfuration to Cys become disturbed. Moreover, in PD the most pronounced alterations in Hcy levels in cases of A1298C polymorphism of *MTHFR* have been manifested in both genotypes AA and AC, even if this has not been expressed by the increased in parallel levels of oxidized guanine in DNA.

The enzyme of MTR is responsible for transfer of methyl groups from methyltetrahyrofolate to Hcy with involvement of methylcobalamin as the cofactor. The AG genetype of the A2756G polymorphism of *MTR* is probably linked to augmented levels of Hcy (Dorszewska et al., 2007). The increase of Hcy concentrations most probably results from lowered activity of MTR, induced by excessive oxidation of cobalamin (McCaddon et al. 2002) due to a more pronounced oxidative stress in degenerative syndromes. In parallel, the studies of Matsuo et al. (2001) indicate that *MTR* AG leads also to hypomethylation of DNA and to inactivation of several genes (low levels of SAM).

It seems also that the polymorphism G1958A of the gene coding for MTHFD1 enzyme may be involved in pathogenesis of PD, and heterozygote as well as homozygote (GA, AA) are thought to be responsible for increased levels of Hcy (Dorszewska et al., 2007). MTHFD1 represents another folate-dependent enzyme, which catalyzes transformation of tetrahydrofolate to 10-formyl, 5,10-methenyl and 5,10-methylene derivatives. 10- Formyltetrahydrofolate and 5,10-methylenetetrahydrofolate are regarded to serve as donors of methyl groups in DNA biosynthesis. The study of Dorszewska et al. (2007) also indicated that significant differences of the levels of Cys/Hcy, *MTHFD1* GA (G1958) were between AD and PD groups. The results indicate that only polymorphisms of folate-dependent enzyme *MTHFD1* have pointed to significant differences in intensity of turnover of circulating thiols between both neurodegenerative diseases, AD and PD.

Some studies confirmed that the C677T *MTHFR* polymorphism should consider as a genetic risk factor in patients who are going to take L-dopa preparations and folates and vitamins B (6, 12) supplementation may be given to the treated PD patients.

developing neurodegenerative diseases are accompanied by disturbed metabolism of Hcy and ADMA and administration of L-arginine, in line with vitamins B6, B12 and folates, to

**4. Polymorphisms of** *MTHFR, MTR, MTHFD1* **and the level of biothiols in** 

The enzyme MTHFR plays a key role in regulating of Hcy metabolism. The study of Yasui et al. (2000) indicated that the TT *MTHFR* C677T genotype might also be linked to pathogenesis of PD, particularly when the level of folates is low. However, Fong et al. (2011) indicated on synergistic effects of polymorphisms in the folate metabolic pathway genes in PD not only C677T *MTHFR*, but also A2756G of *MTR* and A1049G, C1783T of *MTRR* (methionine synthase reductase). Yuan et al. (2009) showed on synergism between Hcy elevation after L-dopa administration in PD patients and *MTHFR,* CT and TT (C677T) genotypes. The study of Dorszewska et al. (2007) indicated that the genotypes TT (C677T), CC (A1298C) and AA (G1793A) of *MTHFR* have been the least frequent in patients with neurodegenerative disorders and their incidence has been slightly increased in the degenerative diseases (e.g. PD). In study of Dorszewska et al. (2007) also indicated that in PD patients Hcy has reached higher levels only in patients with CT genotype of *MTHFR* C677T. It seems that, particularly in persons with CT genotype of the C677T polymorphism of *MTHFR*, processes of Hcy transsulfuration to Cys become disturbed. Moreover, in PD the most pronounced alterations in Hcy levels in cases of A1298C polymorphism of *MTHFR* have been manifested in both genotypes AA and AC, even if this has not been expressed by

The enzyme of MTR is responsible for transfer of methyl groups from methyltetrahyrofolate to Hcy with involvement of methylcobalamin as the cofactor. The AG genetype of the A2756G polymorphism of *MTR* is probably linked to augmented levels of Hcy (Dorszewska et al., 2007). The increase of Hcy concentrations most probably results from lowered activity of MTR, induced by excessive oxidation of cobalamin (McCaddon et al. 2002) due to a more pronounced oxidative stress in degenerative syndromes. In parallel, the studies of Matsuo et al. (2001) indicate that *MTR* AG leads also to hypomethylation of DNA and to inactivation

It seems also that the polymorphism G1958A of the gene coding for MTHFD1 enzyme may be involved in pathogenesis of PD, and heterozygote as well as homozygote (GA, AA) are thought to be responsible for increased levels of Hcy (Dorszewska et al., 2007). MTHFD1 represents another folate-dependent enzyme, which catalyzes transformation of tetrahydrofolate to 10-formyl, 5,10-methenyl and 5,10-methylene derivatives. 10- Formyltetrahydrofolate and 5,10-methylenetetrahydrofolate are regarded to serve as donors of methyl groups in DNA biosynthesis. The study of Dorszewska et al. (2007) also indicated that significant differences of the levels of Cys/Hcy, *MTHFD1* GA (G1958) were between AD and PD groups. The results indicate that only polymorphisms of folate-dependent enzyme *MTHFD1* have pointed to significant differences in intensity of turnover of

Some studies confirmed that the C677T *MTHFR* polymorphism should consider as a genetic risk factor in patients who are going to take L-dopa preparations and folates and vitamins B

circulating thiols between both neurodegenerative diseases, AD and PD.

(6, 12) supplementation may be given to the treated PD patients.

PD patients may offer a modern therapy in this neurodegenerative disease.

the increased in parallel levels of oxidized guanine in DNA.

of several genes (low levels of SAM).

**Parkinson's disease** 
