Atp7b-dependent choroid plexus dysfunction causes transient copper deficit and metabolic changes in the developing mouse brain

Abstract

Copper (Cu) has a multifaceted role in brain development, function, and metabolism. Two homologous Cu transporters, Atp7a (Menkes disease protein) and Atp7b (Wilson disease protein), maintain Cu homeostasis in the tissue. Atp7a mediates Cu entry into the brain and activates Cu-dependent enzymes, whereas the role of Atp7b is less clear. We show that during postnatal development Atp7b is necessary for normal morphology and function of choroid plexus (ChPl). Inactivation of Atp7b causes reorganization of ChPl’ cytoskeleton and cell-cell contacts, loss of Slc31a1 from the apical membrane, and a decrease in the length and number of microvilli and cilia. In ChPl lacking Atp7b, Atp7a is upregulated but remains intracellular, which limits Cu transport into the brain and results in significant Cu deficit, which is reversed only in older animals. Cu deficiency is associated with down-regulation of Atp7a in locus coeruleus and catecholamine imbalance, despite normal expression of dopamine-β-hydroxylase. In addition, there are notable changes in the brain lipidome, which can be attributed to inhibition of diacylglyceride-to-phosphatidylethanolamine conversion. These results identify the new role for Atp7b in developing brain and identify metabolic changes that could be exacerbated by Cu chelation therapy.

Disulfiram downregulates ferredoxin 1 to maintain copper homeostasis and inhibit inflammation in cerebral ischemia/reperfusion injury

“…The displacement of these proteins is specifically triggered by elevated levels of their own ligand, Cu (I), not Cu (II), and is intended to efflux to restore intracellular copper levels 43 – 45 FDX1 helps convert Cu (II) to the more toxic Cu (I), and in our study, DSF inhibited FDX1 expression, reduced Cu (I) levels, and reduced transport of ATP7A and ATP7B. Interestingly, dysregulation of the Cu transport mechanism in the choroid plexus of Atp7b –/– mice has been demonstrated in recent studies; these mice exhibited low Cu levels in the brain at 4 weeks postnatally, emphasizing the crucial role of ATP7B in Cu accumulation 46 . In summary, the inhibition of CTR1 could regulate the cuproptosis pathway by affecting Cu uptake.…”

Addressing the gaps in homeostatic mechanisms of copper and copper dithiocarbamate complexes in cancer therapy: a shift from classical platinum-drug mechanisms

“…124 Lastly, copper is transferred from the cytosol to the TGN lumen by the Cu + -ATPase transporters ATP7A and ATP7B, where it eventually triggers copper-dependent proteins in the secretory pathway. 126…”

The miR‐669a‐5p/G3BP/HDAC6/AKAP12 Axis Regulates Primary Cilia Length

“…To explore how G3BPs regulate cilium length, we performed mass spectrometry to elucidate the protein expression profiles of control cells and G3BP dKO cells after culture in serum‐free medium for 24 h. A total of 105 differentially expressed proteins were identified, including 60 proteins that were significantly upregulated and 45 that were downregulated in G3BP dKO cells relative to control cells (Figure S4A and Table S3, Supporting Information). Among these differentially expressed proteins, we found seven cilium‐related proteins, namely, copper‐transporting ATPase 2 (ATP7B), [ 24 ] collagen alpha‐1 (II) chain (COL2A1), [ 25 ] aspartokinase 1 (AK1), [ 26 ] fatty acid‐binding protein (FABP4), [ 27 ] AKAP12, [ 28 ] serologically defined colon cancer antigen 8 homolog (SDCCAG8), [ 29 ] and pyruvate dehydrogenase (acetyl‐transferring) kinase isozyme 1 (PDK1) (Figure S4B and Table S4, Supporting Information). First, qPCR results showed that the transcript level of SDCCAG8 was downregulated in G3BP dKO cells relative to control cells, which was inconsistent with the mass spectrometry results and that the levels of ATP7B and CoL2A1 were indistinguishable between the two cell lines.…”