Abstract
In Wilson disease, excessive copper accumulates in patients' livers and may, upon serum leakage, severely affect the brain according to current viewpoints. Present remedies aim at avoiding copper toxicity by chelation, for example, by D-penicillamine (DPA) or bis-choline tetrathiomolybdate (ALXN1840), the latter with a very high copper affinity. Hence, ALXN1840 may potentially avoid neurological deterioration that frequently occurs upon DPA treatment. As the etiology of such worsening is unclear, we reasoned that copper loosely bound to albumin, that is, mimicking a potential liver copper leakage into blood, may damage cells that constitute the blood-brain barrier, which was found to be the case in an in vitro model using primary porcine brain capillary endothelial cells. Such blood-brain barrier damage was avoided by ALXN1840, plausibly due to firm protein embedding of the chelator bound copper, but not by DPA. Mitochondrial protection was observed, a prerequisite for blood-brain barrier integrity. Thus, high-affinity copper chelators may minimize such deterioration in the treatment of neurologic Wilson disease.
Highlights
In 1912, Samuel Alexander Kinnier Wilson reported a fatal neurological disease characterized by a progressive degeneration of the lenticular nucleus that was associated with liver cirrhosis [1]
We have demonstrated that intravenously present copper can access the brain supporting vessels (Fig 1) and that upon increase, copper is progressively loosely bound to serum albumin (Fig 2)
This may be realized as counterintuitive because serum albumin has an enormous capacity to tightly bind the metal at a binding site with very high affinity
Summary
In 1912, Samuel Alexander Kinnier Wilson reported a fatal neurological disease characterized by a progressive degeneration of the lenticular nucleus that was associated with liver cirrhosis [1]. We know that Wilson disease (WD) is due to an impairment of the mostly liver-residing copper-transporting ATPase ATP7B [2, 3, 4]. ATP7B defects cause massive liver copper accumulation and current viewpoints state that this copper may leak into the circulation [5]. In the WD animal model toxic milk mouse, there is some experimental evidence for this route. These mice appear with enormous liver copper accumulations, whereas modest elevations are seen in the spleen, kidney, and brain [8]. Upon intragastric D-penicillamine (DPA) administration, within days, a significant increase in copper in the serum and in the brain was demonstrated in these mice [9], and one may conclude that it is the DPA taken up by the portal vein that liberates liver copper to cause serum and brain copper elevations
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