Abstract
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.
Highlights
Niemann-Pick disease type C (NPC) is an autosomal recessive lysosomal storage disorder resulting from mutations in the NPC1 (95% of cases) or NPC2 genes
The %injected dose (ID)/mL values for lung derived from positron emission tomography (PET) were much less than the %ID/g values derived from ex vivo organ counting because
We have investigated in vivo copper trafficking in a mouse model of NPC1 disease at presymptomatic (6 weeks) and symptomatic (9 weeks) stages of the disorder by PET imaging using 64Cu-GTSM in order to identify any measurable changes in copper efflux and distribution associated with the pathology
Summary
Niemann-Pick disease type C (NPC) is an autosomal recessive lysosomal storage disorder resulting from mutations in the NPC1 (95% of cases) or NPC2 genes It is characterised by the accumulation of lysosomal cholesterol and sphingolipids giving rise to liver dysfunction and progressive neurodegeneration, including cerebellar atrophy leading to ataxia. Whole-brain copper levels have not been measured in human brain tissue, but were found to be decreased in NPC1 null mice compared to healthy controls (Hung et al 2014). Copper content in the cerebellum was shown to be reduced or unchanged in NPC1 null mice relative to age-matched controls (Vazquez et al 2012b, Hung et al 2014). An improved understanding of copper trafficking and tissue distribution in NPC1 disease is needed and would greatly facilitate (i) the development of new diagnostic techniques, (ii) the elucidation of the mechanism of disease pathogenesis and progression
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