Multiple aspects of homocysteine neurotoxicity: Glutamate excitotoxicity, kinase hyperactivation and DNA damage

Abstract

Homocysteine (HC) is a neurotoxic amino acid that accumulates in several neurological disorders including Alzheimer's disease (AD). We examined the consequences of treatment of cultured murine cortical neurons with HC. Homocysteine-induced increases in cytosolic calcium, reactive oxygen species, phospho-tau immunoreactivity and externalized phosphatidyl serine (indicative of apoptosis). Homocysteine-induced calcium influx through NMDA channel activation, which stimulated glutamate excitotoxicity, as evidenced by treatment with antagonists of the NMDA channel and metabotropic glutamate receptors, respectively. The NMDA channel antagonist MK-801 reduced tau phosphorylation but not apoptosis after HC treatment, suggesting that HC-mediated apoptosis was not due to calcium influx. Apoptosis after HC treatment was reduced by co-treatment with 3-aminobenazmidine (3ab), an inhibitor of poly-ADP-ribosome polymerase (PARP), consistent with previous reports that ATP depletion by PARP-mediated repair of DNA strand breakage mediated HC-induced apoptosis. Treatment with 3ab did not reduce tau phosphorylation, however, therefore hyperphosphorylation of tau may not contribute to HC-induced apoptosis under these conditions. Inhibition of mitogen-activated protein kinase by co-treatment with the kinase inhibitor PD98059 inhibited tau phosphorylation but not apoptosis after HC treatment. HC accumulation reduces cellular levels of S-adenosyl methionine (SAM); co-treatment with SAM reduced apoptosis, suggesting that inhibition of critical methylation reactions may mediate HC-induced apoptosis. These findings indicate that HC compromises neuronal homeostasis by multiple, divergent routes.

Protein Phosphatase 2A Methyltransferase Links Homocysteine Metabolism with Tau and Amyloid Precursor Protein Regulation

“…The functional implications of changes in tau phosphorylation are numerous, because epitope-specific phosphorylation differentially modulates the distribution, degradation, aggregation, binding to microtubules and other proteins such as PP2A, and microtubuleregulatory functions of tau (Brandt et al, 2005;Stoothoff and Johnson, 2005). It has been reported that exogenous Hcy and folate deficiency in cultured neurons can increase SAH and/or decrease SAM levels and promote tau phosphorylation (Ho et al, 2002(Ho et al, , 2003. Our studies show that some of these effects are directly mediated by PP2A.…”

No association between MTHFR A1298C and MTRR A66G polymorphisms, and MS in an Australian cohort

“…Other investigations also support the finding of elevated homocysteine levels in MS patients compared with healthy controls [20], [21] and [22]. It is hypothesized that the nervous system may be particularly sensitive to pHcy as it promotes excitotoxicity by stimulation of NMDA receptors and damages neuronal DNA hence triggering apoptosis in neuronal cells [14] and [23]. Ergo, although our findings suggest no association between MTHFR A1298C and MTRR A66G and MS, other variants associated with the homocysteine metabolism cascade may still contribute to MS susceptibility.…”

Homocysteine, methylenetetrahydrofolate reductase and risk of schizophrenia: a meta-analysis

“…51,52 Extra-cellular homocysteine has been found to be toxic to cultured neurons and neuron cells via stimulation of NMDA receptors, enhancing oxidative stress and inducing DNA damage eventually resulting in apoptosis and adverse effects on synaptic and glial function. 51,53,54 Recently, experiments with mice have shown that these mechanisms are not only important in cultured embryonic premitotic neurons, but in the adult postmitotic neurons as well. 55 The deleterious effect of MTHFR dysfunction on brain development was observed in individuals with a severe deficiency of this enzyme, resulting in delayed psychomotor development, mental retardation and psychiatric symptoms.…”