Homocysteine induces cytotoxicity and proliferation inhibition in neural stem cells via DNA methylation in vitro

Abstract

Mild to moderate hyperhomocysteinemia has been implicated in neurodevelopmental disorders and neurodegenerative diseases in human studies. Although the molecular mechanisms underlying the effects of homocysteine (Hcy) neurotoxicity on the nervous system are not yet fully understood, inhibition of neural stem cell (NSC) proliferation and alterations in DNA methylation may be involved. The aim of the present study was to characterize the effects of Hcy on DNA methylation in NSCs, and to explore how Hcy-induced changes in DNA methylation patterns affect NSC proliferation. We found that D,L-Hcy (30-1000 lM) but not L-cysteine inhibited cell proliferation and reduced levels of global DNA methylation in NSCs from neonatal rat hippocampus and increased cell injury. High levels of Hcy also induced an increase in S-adenosylhomocysteine (SAH), a decrease in the ratio of S-adenosylmethionine (SAM) to SAH, and a reduction in protein expression of the DNA methyltransferases DNMT1, DNMT3a and DNMT3b and their enzymatic activity. Moreover, the DNMT inhibitor zebularine reduced the global DNA methylation level and inhibited NSC proliferation. Our results suggest that alterations in DNA methylation may be an important mechanism by which high levels of Hcy inhibit NSC viability in vitro. Hcy-induced DNA hypomethylation may be caused by a reduction in the DNMT activity which is regulated by the cellular concentrations of SAM and SAH, or their protein expression levels. Our results also suggest that Hcy may play a role in the pathogenesis of certain nervous system diseases via a molecular mechanism that involves negative regulation of NSC proliferation and alterations in DNA methylation.

Assessment of Homocysteine as a Diagnostic and Early Prognostic Biomarker for Patients with Acute Lacunar Infarction

“…It has been reported that high levels of Hcy induced DNA hypomethylation by a reduction in the DNA methyltransferase activity and then inhibited neural stem cell proliferation [31], thus inducing neurological deterioration. This hypothesis has been observed in several clinical studies, with the high levels of serum Hcy as independent predictors for END for stroke patients [11, 14].…”

Folic acid administration inhibits amyloid β-peptide accumulation in APP/PS1 transgenic mice

“…The excessive SAH may inhibit DNMT and thereby contribute to hypomethylation of DNA [24,25]. Also, elevated HCY concentration is associated with memory impairment in mouse models of AD [26] and the induction of cytotoxicity and inhibited cell proliferation in neural stem cells [27]. Folate may confer neuroprotection because it acts as a cofactor in the elimination of HCY by the latter's remethylation [3].…”

Metabolic Risk Factors of Sporadic Alzheimer's Disease: Implications in the Pathology, Pathogenesis and Treatment

“…Several casecontrol studies have shown that the degree of hyperhomocysteinemia is more in typical vascular dementia than in AD [129,130]. Nevertheless, many experimental studies have shown that homocysteine in higher than physiological concentrations can induce a wide range of neurotoxic effects involving oxidative stress, excitotoxicity, mitochondrial dysfunction, DNA damage and apoptosis implying that hyperhomocysteinemia may directly contribute to AD neurodegeneration [117,131,132,133].…”