Role of zinc transporter ZIP12 in susceptibility‐weighted brain magnetic resonance imaging (MRI) phenotypes and mitochondrial function

Abstract

Brain zinc dysregulation is linked to many neurological disorders. However, the mechanisms regulating brain zinc homeostasis are poorly understood. We performed secondary analyses of brain MRI GWAS and exome sequencing data from adults in the UK Biobank. Coding ZIP12 polymorphisms in zinc transporter ZIP12 (SLC39A12) were associated with altered brain susceptibility weighted MRI (swMRI). Conditional and joint association analyses revealed independent GWAS signals in linkage disequilibrium with 2 missense ZIP12 polymorphisms, rs10764176 and rs72778328, with reduced zinc transport activity. ZIP12 rare coding variants predicted to be deleterious were associated with similar impacts on brain swMRI. In Neuro‐2a cells, ZIP12 deficiency by short hairpin RNA (shRNA) depletion or CRISPR/Cas9 genome editing resulted in impaired mitochondrial function, increased superoxide presence, and detectable protein carbonylation. Inhibition of Complexes I and IV of the electron transport chain reduced neurite outgrowth in ZIP12 deficient cells. Transcriptional coactivator PGC‐1α, mitochondrial superoxide dismutase (SOD2), and chemical antioxidants α‐tocopherol, MitoTEMPO, and MitoQ restored neurite extension impaired by ZIP12 deficiency. Mutant forms of α‐synuclein and tau linked to familial Parkinson’s disease and frontotemporal dementia, respectively, reduced neurite outgrowth in cells deficient in ZIP12. Zinc and ZIP12 may confer resilience against neurological diseases or premature aging of the brain.

Brain Magnetic Resonance Imaging Phenome-Wide Association Study With Metal Transporter Gene SLC39A8

“…Of the 14 ZIP members, only ZIP8, ZIP12, and ZIP14 have brain MRI phenotypes that meet the significance threshold set for this PheWAS. ZIP12 is linked to swMRI intensity in the caudate, putamen, and pallidum and to gray matter putamen (Strong et al, 2020), which is similar to the brain MRI phenotypes tied to ZIP8. ZIP14 is associated with differences in gray matter (T1 FAST) in the right ventral striatum and cortical thickness (Freesurfer) of the left orbital lateral area.…”

“…If the differences in swMRI intensity associated with rs13107325 are due to altered iron transport, it is possible that high brain iron may promote brain development early in life but increase susceptibility to neurodegeneration or brain aging in later adulthood. Polymorphisms and rare inactivating mutations in zinc transporter ZIP12 are associated with swMRI differences in the basal ganglia (Strong et al, 2020), which suggests that altered intracellular zinc dynamics may also impact brain swMRI intensity. More studies are needed to determine what metals are responsible for the swMRI differences due to ZIP8 polymorphisms.…”

“…To identify the independent association signals present at each locus, we used GCTA-COJO software to perform conditional and joint association analyses (Yang et al, 2012) across Chromosome 4 as we have performed previously for Chromosome 10 (Strong et al, 2020). Summary statistic datasets for the 24 brain MRI phenotypes were downloaded from the website http://big.stats.…”

“…Rare variant data was obtained from whole exome datasets of European ancestry in the UK Biobank with brain MRI data (Cirulli et al, 2020) as we have performed previously (Strong et al, 2020). A collapsing method (Li and Leal, 2008) added all variants with a MAF less than 0.001 and included coding or splice variants predicted by SIFT or PolyPhen-2 to be not tolerated or not benign and loss of function variants including frameshift, stop gain, start lost, splice acceptor, and splice donor mutations.…”

Quantitative MRI susceptibility mapping reveals cortical signatures of changes in iron, calcium and zinc in malformations of cortical development in children with drug-resistant epilepsy

“…Zinc is involved in many biochemical processes and is a crucial micronutrient necessary for normal brain functions ( Mocchegiani et al., 2005 ; Strong et al., 2020 ). The mechanism by which zinc is taken up in the brain parenchyma cells is poorly understood ( Takeda, 2000 ).…”