Localization of copper and copper transporters in the human brain

Abstract

Disturbances in brain copper result in rare and severe neurological disorders and may play a role in the pathogenesis and progression of multiple neurodegenerative diseases. Our current understanding of mammalian brain copper transport is based on model systems outside the central nervous system and no data are available regarding copper transport systems in the human brain. To address this deficit, we quantified regional copper concentrations and examined the distribution and cellular localization of the copper transport proteins Copper transporter 1, Atox1, ATP7A, and ATP7B in multiple regions of the human brain using inductively coupled plasma-mass spectrometry, Western blot and immunohistochemistry. We identified significant relationships between copper transporter levels and brain copper concentrations, supporting a role for these proteins in copper transport in the human brain. Interestingly, the substantia nigra contained twice as much copper than that in other brain regions, suggesting an important role for copper in this brain region. Furthermore, ATP7A levels were significantly greater in the cerebellum, compared with other brain regions, supporting an important role for ATP7A in cerebellar neuronal health. This study provides novel data regarding copper regulation in the human brain, critical to understand the mechanisms by which brain copper levels can be altered, leading to neurological disease.

Ferritin iron uptake and release in the presence of metals and metalloproteins: Chemical implications in the brain

“…substantia nigra accumulates twice as much Cu as the surrounding brain regions (Fig. 7) [122]. Copper in the brain is mainly associated with holoenzymes, transporters and chaperones, and homeostatic proteins [123].…”

“…Copper in the brain is mainly associated with holoenzymes, transporters and chaperones, and homeostatic proteins [123]. Cu-containing enzymes are mainly involved in cell respiration, iron metabolism, ROS defense mechanisms, and significantly, the synthesis of neurotransmitters (dopamine [124]) and neuron myelinization [122].…”

Expression and localization of the copper-ATPase ATP7A in mice neural cells

“…Moreover, astrocytes have a higher level of ATP7A than neurons (Figure 2A), revealing a powerful capability of copper regulation in astrocytes to protect neurons from copper toxicity and deficiency (Scheiber et al 2012;Scheiber & Dringen 2013). The immunocytochemistry analysis displayed the typical pattern of perinuclear ATP7A distribution under the low-copper conditions (Figure 3), in which ATP7A fulfilled its main function to deliver copper for incorporation into copper-dependent enzymes (Iwase et al 1996;Davies et al 2013;Scheiber & Dringen 2013). ATP7A immunoreactivity was absent from neuron axons and dendrites ( Figure 3C), while it was ample in mature primary hippocampal neurons (Schlief et al 2005) and olfactory receptor neurons (Meskini et al 2005).…”

“…ATP7A is widely expressed throughout the brain, but shows significant differences in different regions of the brain such as greater levels in the brain barriers and cerebellum than in other brain regions (Qian et al 1998;Choi & Zheng 2009;Davies et al 2013). In addition, research on immunohistochemistry and hybridization in situ showed that expression of ATP7A is regulated spatially and temporally by nervous system development.…”

Abnormal Copper Homeostasis: Mechanisms and Roles in Neurodegeneration

“…Figure 1 illustrates the metabolism of copper in the brain. Brain concentrations range from 3.1 to 5.1 mg/g wet weight [11,12]. Within the brain, the distribution of copper is heterogeneous.…”