Role of S-adenosylmethionine in the Modulation of Oxidative Stress- Related Neurodegeneration

Abstract

S-adenosyl-L-methionine (SAM) is the main biological methyl donor in transmethylation reactions, consisting in the transferring of a methyl moiety to different substrates including DNA, proteins, lipids and RNA. SAM level in the organism decreases with aging and restoring the original levels through exogenous supplementation is an important tool for the improvement of many vital functions. Indeed, SAM deficiency may contribute to the onset of several diseases, i.e. depression, liver diseases, osteoarthritis and senile neurological disorders such as Alzheimer's and Parkinson's diseases. Recent evidences indicate that SAM may have an involvement in oxidative stress, a process which typically involves an alteration of cellular sulfur amino acids homeostasis. SAM is not only the principal methyl donor, but also a precursor of glutathione, the major endogenous antioxidant, whose role in counteracting oxidative stress is well known. In this review we will highlight the role of SAM not just as a methyl-donor but also as a regulator of different metabolic pathways involved in the antioxidant response in brain related disorders. Role of S-adenosylmethionine in the Modulation of Oxidative StressRelated Neurodegeneration Review ArticleOpen Access IntroductionThe interaction between environmental and genetic factors plays a fundamental role in inducing and modulating the aging processes towards brain disorders. Among environmental factors, diet and nutritional lifestyle have a key role in brain health through the alteration of the intake or the bioavailability of metabolites and cofactors. Specific nutritional factors have particular impact on one-carbon metabolism, which is a complex biochemical pathway regulated by the presence of folate, vitamin B12 and B6 (among other metabolites) and leading to the production of S-adenosyl-L-methionine (SAM), the main biological methyl donor in transmethylation reactions, consisting in the transferring of a methyl moiety to different substrates including DNA, proteins, lipids and RNA. This metabolism involves three interrelated biochemical pathways: folate cycle, transsulfuration pathway and methionine cycle. These three metabolic sequences were first combined and correlated in 1964 by Laster's group [1][2][3] giving the integrated point of view of transmethylation and transsulfuration pathways, linking sulfur amino acid metabolism to the provision of methyl groups for many biochemical processes. Normal functioning of this metabolic cycle is essential for growth and development and impairment of this metabolism; transmethylation efficiency is associated with many diseases like cardiovascular diseases [4][5], liver diseases [6-9], neural tube defects [10] and brain diseases [11][12][13][14][15][16]. One-carbon metabolism alterations, low methylation and oxidative stress are all linked to Late Onset Alzheimer's Disease (LOAD) [17][18][19][20][21][22][23][24] Moreover, wide confirmed reports underline the role of SAM dependent reactions in age related neurodegeneration also showi...

Reduced uremic metabolites are prominent feature of sarcopenia, distinct from antioxidative markers for frailty

“…Moreover, the decrease of several methylated compounds is an unexpected feature of sarcopenia. S-adenosyl methionine (SAM) is the major methyl-group donor in methylation of DNA, histones, proteins, lipids, and RNA [ 53 ]. However, as SAM does not decrease significantly in sarcopenia, some other muscle- or tissue-specific methylation pathway component may be impaired in sarcopenia.…”

Betaine attenuates pathology by stimulating lipid oxidation in liver and regulating phospholipid metabolism in brain of methionine‐choline–deficient rats

“…Methyl-donor deficiency is not only associated with liver disease but also with neurodegenerative diseases ABBREVIATIONS: 4-HNE, 4-hydroxynonenal; AADD, amino acid-defined diet; AC, acylcarnitine; AD, Alzheimer's disease; ALT, alanine aminotransferase; BHMT, betaine-Hcy S-methyltransferase; Cbs, cystathionineb-synthase; Cpt1, carnitine palmitoyltransferase 1; EPM, elevated plus maze; FC, free carnitine; Fgf21, fibroblast growth factor 21; Hcy, homocysteine; H&E, hematoxylin and eosin; lysoPC a, lysophosphatidylcholine acyl; MCD, methionine-choline deficient; MCD+B, betaine-supplemented MCD; MWM, Morris water maze; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NOR, novel object recognition; PC, phosphatidylcholine; PC aa, diacyl PC; PC ae, acyl-alkyl PC; PE, phosphatidylethanolamine; PEMT, PE N-methyltransferase; Pgc1a, peroxisome proliferator-activated receptor-g coactivator; PL, phospholipid; PLC, palmitoylcarnitine; Ppara, peroxisome proliferator-activated receptor a; SAH, S-adenosyl-Hcy; SAM, S-adenosyl-methionine; SD, Sprague-Dawley; SM, sphingomyelin; SM(OH), hydroxySM; tHcy, total Hcy; VLDL, very low density lipoprotein (5,6). Impairment of methylation metabolism in older humans, as indicated by elevated plasma total homocysteine (tHcy), is a prevalent risk factor for stroke, mild cognitive impairment, Alzheimer's disease (AD), and dementia in general (7).…”

Metabolic and immune responses of Chinook salmon (Oncorhynchus tshawytscha) smolts to a short‐term poly (I:C) challenge

“…Upregulated levels of SAH in poly (I:C)-treated fish were observed, indicating the reduced use of SAH to form glutathione and the consequent conversion to methionine via methylation by betaine or methylated folic acid pathways (Olsvik et al, 2017). Also, the upregulation of (Cavallaro et al, 2016). Indeed, cysteine and methionine levels were upregulated in the poly (I:C)-treated fish, indicating an enhanced immune response to supply these metabolites for the transsulphuration and glutathione pathways in response to increases in ROS production in the treated fish, as previously demonstrated elsewhere (Levine et al, 1999;Séité et al, 2018;Wu et al, 2012).…”