Rethinking the zinc-copper relationship in Wilson Disease

Wilson Disease (WD) is an inherited disorder of copper (Cu) metabolism that results in pathogenic Cu
accumulation in the liver and brain as well as secondary organ damage largely related to liver injury. WD
diagnosis and treatment are challenging, while an important gap in treatment includes a lack of measurable
biomarkers that specifically report on treatment. An estimated 1:100 people carry a pathogenic mutation in the
ATP7B Cu transporter that is deficient in WD, while the global prevalence estimate for WD is 1:30,000, with
higher prevalence in specific communities (e.g., Canary Islands 1:2,600 and South Korea 1:3,500). The current
understanding of WD progression is that pathogenesis develops from damage to the liver and its key functions.
Cu excess is expected to induce oxidative damage to cellular structures; this injury appears to be more
important later in disease progression, while the early and specific molecular effects of Cu accumulation appear
to be in liver metabolic function, specifically lipid metabolism and mitochondrial activity. WD treatments can
be classified as either zinc (Zn) salts or Cu chelators. Poor response to these therapies necessitates liver
transplant. One major challenge in successful treatment is a lack of compliance, which is influenced by adverse
side effects or cumbersome therapeutic schedules. Treatment sometimes induces paradoxical neurological
deterioration. Given these challenges, knowledge of biomarkers that respond to treatment will be valuable to
personalize WD therapy. Recent work, including our own, indicates that Zn-containing proteins are specifically
affected in WD and that liver metabolic processes, many regulated by Zn proteins, are changed. The proposed
work will build on this knowledge to define candidate biomarkers responsive to WD treatment. We will
leverage a well-characterized WD mouse model in a treatment study to identify metabolite, gene expression
and metal responses in liver and serum that are induced by Cu chelator or Zn treatments. The project executes
the following Specific Aims: 1) Define treatment-responsive metabolite biomarkers induced by Cu chelator or
Zn treatment in the Atp7b-/- mouse model of WD. Prior work has identified candidate biomarkers of WD in
mice and humans, but these biomarkers are indicative of several liver diseases. Our approach will define
candidate markers in liver and serum that respond specifically to WD treatment. 2) Determine sex-specific
transition metal responses to WD treatments. Both animal models and humans appear to have sex-
differentiated Cu and Zn homeostatic control, indicating it is important to understand how WD treatments
have differential impacts by sex. 3) Define Cu and Zn interactions in cell health. Crosstalk between Cu and Zn is
not well defined and may be important beyond WD treatment. This aim will use a non-WD hepatoma cell and
wild-type mouse models to determine impacts of Cu chelation or zinc supplementation. This translational
project will leverage existing data and a new, rich, sex-specific, dataset of metabolites, metals, and cellular Cu-
Zn interactions to identify candidate biomarkers for enhancement of WD treatment.

Grant Number: 2R15DK114747-02
NIH Institute/Center: NIH
Principal Investigator: JASON BURKHEAD