Wilson disease at a single cell level: intracellular copper trafficking activates compartment-specific responses in hepatocytes.
Wilson disease (WD) is a severe hepato-neurologic disorder that affects primarily children and young adults. WD is caused by mutations in ATP7B and subsequent copper overload. However, copper levels alone do not predict severity of the disease. We demonstrate that temporal and spatial distribution of copper in hepatocytes may play an important role in WD pathology. High resolution synchrotron-based x-ray fluorescence imaging in situ indicates that copper does not continuously accumulate in Atp7b(-/-) hepatocytes, but reaches a limit at 90-300 fmol. The lack of further accumulation is associated with the loss of copper transporter Ctr1 from the plasma membrane and the appearance of copper-loaded lymphocytes and extracellular copper deposits. The WD progression is characterized by changes in subcellular copper localization and transcriptome remodeling. The synchrotron-based x-ray fluorescence imaging and mRNA profiling both point to the key role of nucleus in the initial response to copper overload and suggest time-dependent sequestration of copper in deposits as a protective mechanism. The metabolic pathways, up-regulated in response to copper, show compartmentalization that parallels changes in subcellular copper concentration. In contrast, significant down-regulation of lipid metabolism is observed at all stages of WD irrespective of copper distribution. These observations suggest new stage-specific as well as general biomarkers for WD. The model for the dynamic role of copper in WD is proposed.
Ralle
Martina
M
Department of Biochemistry and Molecular Biology, Oregon Health & Science University, Portland, Oregon 97239, USA. rallem@ohsu.edu
Huster
Dominik
D
Vogt
Stefan
S
Schirrmeister
Wiebke
W
Burkhead
Jason L
JL
Capps
Tony R
TR
Gray
Lawrence
L
Lai
Barry
B
Maryon
Edward
E
Lutsenko
Svetlana
S
D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D003300:Copper / Q000378:metabolism*; D000079923:Copper Transporter 1; D000073840:Copper-Transporting ATPases; D004195:Disease Models, Animal; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D006527:Hepatolenticular Degeneration / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout
C486201:Atp7a protein, mouse; D015415:Biomarkers; D027682:Cation Transport Proteins; D000079923:Copper Transporter 1; C490077:Slc31a1 protein, mouse; D003300:Copper; D000251:Adenosine Triphosphatases; D000073840:Copper-Transporting ATPases