The Atp7b-/- mouse model of neurological copper toxicity and Wilson Disease - Wilson Disease (WD) is an inherited disorder of copper metabolism caused by mutation in the ATP7B gene
that causes pathogenic copper accumulation in the brain and liver. WD neurologic symptoms can be severe or
fatal and include dystonia, ataxia and Parkinson-like tremor. Patients often present a combination of features.
WD patients may also present with psychiatric symptoms (often prior to WD diagnosis) including behavioral
changes, personality changes, anxiety and depression. A major challenge in WD treatment is that neurological
symptoms often worsen when copper-lowering drugs such as D-penicillamine are administered. Zinc salts are
an alternative treatment for WD and less associated with neurological degradation. However, treatment
efficacy of zinc for liver disease appears to be limited, and improvement in neurologic symptoms is
comparatively slow. A significant obstacle in research on neurologic WD treatment is the limited development
of pre-clinical animal models to study disease mechanisms and treatments. Rodent models of WD have been
invaluable to define hepatic mechanisms of copper toxicosis, while utility in neurologic WD is not well
explored. The Atp7b-/- mouse is a highly characterized rodent model of WD liver pathology, revealing defects in
lipid metabolism, liver damage and relative age-of-onset compared to humans. We recently used this model to
identify altered zinc metabolism as mechanism of copper toxicity in WD. Brain copper in the Atp7b-/- mouse
increases throughout life, which parallels brain copper accumulation in WD patients. This work will determine
the utility of the Atp7b-/- mouse for pre-clinical studies of neurologic WD. Proposed experiments will define
behavioral and molecular responses of altered brain copper levels as well as the impacts of WD treatments on
these phenotypes. An integrative approach will test the hypothesis that the Atp7b-/- mouse models neurologic
WD for mechanistic disease and treatment studies. This hypothesis will be tested through execution of the
following three Specific Aims: Aim 1: Determine the extent to which Atp7b-/-, Atp7b+/- mice exhibit motor
and behavioral impairments. Behavioral phenotypes will be determined for male and female animals of both
wildtype/heterozygous (Atp7b+/+/Atp7b+/-) and knockout (Atp7b-/-) genotypes for three treatment conditions
(untreated, D-penicillamine, or zinc); Aim 2: Determine the effects of Zn or D-penicillamine treatment on the
concentration of trace metals and markers of oxidative stress in the brain for Atp7b-/-, Atp7b+/- and wild type
mice; Aim 3: Determine the changes in Cu and Zn handling protein levels in target brain regions of animals
subjected to control, Zn or chelator treatments. Completion of this study will provide a foundation for
treatment-focused experiments in the Atp7b-/- mouse and WD patients to improve patient outcomes.
Identifying effects of copper toxicity in the brain will also build insight into other neurological disorders with
copper accumulation including Parkinson’s and Alzheimer’s diseases.
