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 ATPase 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, 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 intraperi-toneal injections of 200μg/g body weight of L-DOPS, or mock solution. Five hours after the final injection, the mice were euthanized and brains 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 (DHPG, 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. Interpretation 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.

Peptidylglycine α‐amidating monooxygenase heterozygosity alters brain copper handling with region specificity

“…; Donsante et al . ). As in other cell types, Atp7a trafficking in neurons is responsive to Cu (Schlief et al .…”

Molecular basis of neurodegeneration and neurodevelopmental defects in Menkes disease

“…Mice homozygous for null alleles of PAM and DBH enzymes neither recapitulate the neurodevelopmental nor the neurodegenerative phenotypes observed in Menkes though the mice die in utero (Czyzyk et al, 2005; Thomas et al, 1995) (Table 1). Consistent with these observations, embryonic lethality caused by DBH deficiency in mice can be rescued by systemic administration of L-threo-dihydroxyphenylserine, and while this treatment corrects brain neurochemical abnormalities in Menkes mice, it does not correct neurodegeneration (Donsante et al, 2013). PAM haploinsufficiency impairs long-term potentiation without neurodegeneration or abnormalities in cortical development (Gaier et al, 2010).…”

Molecular and biochemical characterization of Mottled-dappled, an embryonic lethal Menkes disease mouse model

“…The homogenates were centrifuged and supernatant frozen at −80°C until assay. Concentrations of brain neurochemicals dihydroxyphenylalanine (DOPA), DOPAC, DA, NE, and DHPG were determined by high-performance liquid chromatography with electrochemical detection, as previously described [16, 17]. …”