title: L-threo-dihydroxyphenylserine corrects neurochemical abnormalities in a Menkes disease mouse model.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Unit on Human Copper Metabolism, Molecular Medicine Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Rockville, MD 20892-1853, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Donsante
authors.forename: Patricia
authors.initials: P
authors.lastname: Sullivan
authors.forename: David S
authors.initials: DS
authors.lastname: Goldstein
authors.forename: Lauren R
authors.initials: LR
authors.lastname: Brinster
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Kaler
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000978:Antiparkinson Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001923:Brain Chemistry / Q000187:drug effects* / Q000502:physiology; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D003300:Copper / Q000378:metabolism; D000073840:Copper-Transporting ATPases; D004195:Disease Models, Animal; D004298:Dopamine / Q000096:biosynthesis / Q000378:metabolism; D004299:Dopamine beta-Hydroxylase / Q000378:metabolism; D015103:Droxidopa / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D008297:Male; D007706:Menkes Kinky Hair Syndrome / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009638:Norepinephrine / Q000096:biosynthesis / Q000172:deficiency / Q000378:metabolism
chemical_list: D000978:Antiparkinson Agents; C486201:Atp7a protein, mouse; D027682:Cation Transport Proteins; D015102:3,4-Dihydroxyphenylacetic Acid; D003300:Copper; D004299:Dopamine beta-Hydroxylase; D000251:Adenosine Triphosphatases; D000073840:Copper-Transporting ATPases; D015103:Droxidopa; D004298:Dopamine; D009638:Norepinephrine