Activation of methionine synthase by insulin-like growth factor-1 and dopamine: a target for neurodevelopmental toxins and thimerosal

[Guest guest]

http://www.nationalautismassociation.org/library/dethwaly.pdf

Molecular Psychiatry

April 2004, Volume 9, Number 4, Pages 358-370

Activation of methionine synthase by insulin-like growth factor-1 and

dopamine: a target for neurodevelopmental toxins and thimerosal

M Waly1, H Olteanu2, R Banerjee2, S-W Choi3, J B Mason3, B S 4, S

Sukumar4, S Shim1, A Sharma1, J M Benzecry1, V-A Power-Charnitsky1 and R C

Deth1

1Department of Pharmaceutical Sciences, Northeastern University, Boston, MA

02115, USA

2Biochemistry Department, University of Nebraska, Lincoln, NE 68588, USA

3Vitamin Metabolism Laboratory, USDA Human Nutrition Research Center on

Aging at Tufts University, Boston, MA 02111, USA

4Sidney Kimmel Comprehensive Cancer Center at s Hopkins, Baltimore, MD

21231, USA

Correspondence to: RC Deth, Northeastern University, 312 Mugar Hall, 360

Huntington Avenue, Boston, MA 02115, USA. E-mail: r.deth@...

Abstract

Methylation events play a critical role in the ability of growth factors to

promote normal development. Neurodevelopmental toxins, such as ethanol and

heavy metals, interrupt growth factor signaling, raising the possibility

that they might exert adverse effects on methylation. We found that

insulin-like growth factor-1 (IGF-1)- and dopamine-stimulated methionine

synthase (MS) activity and folate-dependent methylation of phospholipids in

SH-SY5Y human neuroblastoma cells, via a PI3-kinase- and

MAP-kinase-dependent mechanism. The stimulation of this pathway increased

DNA methylation, while its inhibition increased methylation-sensitive gene

expression. Ethanol potently interfered with IGF-1 activation of MS and

blocked its effect on DNA methylation, whereas it did not inhibit the

effects of dopamine. Metal ions potently affected IGF-1 and

dopamine-stimulated MS activity, as well as folate-dependent phospholipid

methylation: Cu2+ promoted enzyme activity and methylation, while Cu+, Pb2+,

Hg2+ and Al3+ were inhibitory. The ethylmercury-containing preservative

thimerosal inhibited both IGF-1- and dopamine-stimulated methylation with an

IC50 of 1 nM and eliminated MS activity. Our findings outline a novel growth

factor signaling pathway that regulates MS activity and thereby modulates

methylation reactions, including DNA methylation. The potent inhibition of

this pathway by ethanol, lead, mercury, aluminum and thimerosal suggests

that it may be an important target of neurodevelopmental toxins.

Molecular Psychiatry (2004) 9, 358-370. doi:10.1038/sj.mp.4001476

Published online 27 January 2004