Imaging of changes in copper trafficking and redistribution in a mouse model of Niemann-Pick C disease using positron emission tomography

摘要

Niemann-Pick C disease (NPC) is an autosomal recessive lysosomal storage disorder resulting from mutations in the NPC1 (95% of cases) or NPC2 genes. Disturbance of copper homeostasis has been reported in NPC1 disease. In this study we have used whole-body positron emission tomography (PET) and brain electronic autoradiography with copper-64 (⁶⁴Cu), in the form of the copper(II) bis(thiosemicarbazonato) complex ⁶⁴Cu-GTSM, to image short-term changes in copper trafficking after intravenous injection in a transgenic mouse model of NPC1 disease. ⁶⁴Cu-GTSM is taken up in all tissues and dissociates rapidly inside cells, allowing monitoring of the subsequent efflux and redistribution of ⁶⁴Cu from all tissues. Significantly enhanced retention of ⁶⁴Cu radioactivity was observed in brain, lungs and blood at 15 h post-injection in symptomatic Npc1^−/− transgenic mice compared to wildtype controls. The enhanced retention of ⁶⁴Cu in brain was confirmed by electronic autoradiography, particularly in the midbrain, thalamus, medulla and pons regions. Positron emission tomography imaging with ⁶⁴Cu in selected chemical forms could be a useful diagnostic and research tool for the management and understanding of NPC1 disease.