Homocysteine Level and Mechanisms of Injury in Parkinson's Disease as Related to MTHFR, MTR, and MTHFD1 Genes Polymorphisms and LDopa Treatment
Pawel P. Jagodzinski,
An elevated concentration of total homocysteine (tHcy) in plasma and cerebrospinal fluid is considered to be a
risk factor for Alzheimer's disease (AD) and Parkinson's disease (PD). Homocysteine (Hcy) levels are influenced by folate
concentrations and numerous genetic factors through the folate cycle, however, their role in the pathogenesis of PD remains
controversial. Hcy exerts a neurotoxic action and may participate in the mechanisms of neurodegeneration, such as
excitotoxicity, oxidative stress, calcium accumulation, and apoptosis. Elevated Hcy levels can lead to prooxidative activity,
most probably through direct interaction with N-methyl-D-aspartate (NMDA) receptors and sensitization of dopaminergic
neurons to age-related dysfunction and death. Several studies have shown that higher concentration of Hcy in
PD is related to long-term administration of levodopa (L-dopa). An elevation of plasma tHcy levels can also reflect deficiencies
of cofactors in remethylation of Hcy to methionine (Met) (folates and vitamin B12) and in its transsulfuration to
cysteine (Cys) (vitamin B6). It is believed that the increase in the concentration of Hcy in PD can affect genetic polymorphisms
of the folate metabolic pathway genes, such as MTHFR (C677T, A1298C and G1793A), MTR (A2756G), and
MTHFD1 (G1958A), whose frequencies tend to increase in PD patients, as well as the reduced concentration of B vitamins.
In PD, increased levels of Hcy may lead to dementia, depression and progression of the disease.
Keywords: MTHFR, MTR, MTHFD1 polymorphism, Biothiols, PD.
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