L-Threo-Dihydroxyphenylserine corrects neurochemical abnormalities in a menkes disease mouse model
Article first published online: 7 DEC 2012
Copyright © 2012 American Neurological Association
Annals of Neurology
Volume 73, Issue 2, pages 259–265, February 2013
How to Cite
Donsante, A., Sullivan, P., Goldstein, D. S., Brinster, L. R. and Kaler, S. G. (2013), L-Threo-Dihydroxyphenylserine corrects neurochemical abnormalities in a menkes disease mouse model. Ann Neurol., 73: 259–265. doi: 10.1002/ana.23787
- Issue published online: 22 MAR 2013
- Article first published online: 7 DEC 2012
- Accepted manuscript online: 30 OCT 2012 01:37PM EST
- Manuscript Accepted: 5 OCT 2012
- Manuscript Revised: 21 SEP 2012
- Manuscript Received: 14 AUG 2012
Menkes disease is a lethal neurodegenerative disorder of infancy caused by mutations in a copper-transporting adenosine triphosphatase gene, ATP7A. Among its multiple cellular tasks, ATP7A transfers copper to dopamine beta hydroxylase (DBH) within the lumen of the Golgi network or secretory granules, catalyzing the conversion of dopamine to norepinephrine. In a well-established mouse model of Menkes disease, mottled-brindled (mo-br), we tested whether systemic administration of L-threo-dihydroxyphenylserine (L-DOPS), a drug used successfully to treat autosomal recessive norepinephrine deficiency, would improve brain neurochemical abnormalities and neuropathology.
At 8, 10, and 12 days of age, wild-type and mo-br mice received intraperitoneal injections of 200μg/g body weight of L-DOPS, or mock solution. Five hours after the final injection, the mice were euthanized, and brains were removed. We measured catecholamine metabolites affected by DBH via high-performance liquid chromatography with electrochemical detection, and assessed brain histopathology.
Compared to mock-treated controls, mo-br mice that received intraperitoneal L-DOPS showed significant increases in brain norepinephrine (p < 0.001) and its deaminated metabolite, dihydroxyphenylglycol (p < 0.05). The ratio of a non–beta-hydroxylated metabolite in the catecholamine biosynthetic pathway, dihydroxyphenylacetic acid, to the beta-hydroxylated metabolite, dihydroxyphenylglycol, improved equivalently to results obtained previously with brain-directed ATP7A gene therapy (p < 0.01). However, L-DOPS treatment did not arrest global brain pathology or improve somatic growth, as gene therapy had.
We conclude that (1) L-DOPS crosses the blood–brain barrier in mo-br mice and corrects brain neurochemical abnormalities, (2) norepinephrine deficiency is not the cause of neurodegeneration in mo-br mice, and (3) L-DOPS treatment may ameliorate noradrenergic hypofunction in Menkes disease. ANN NEUROL 2013;73:259–265