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Publication : The schizophrenia-associated variant in SLC39A8 alters protein glycosylation in the mouse brain.

First Author  Mealer RG Year  2022
Journal  Mol Psychiatry Volume  27
Issue  3 Pages  1405-1415
PubMed ID  35260802 Mgi Jnum  J:341580
Mgi Id  MGI:7541239 Doi  10.1038/s41380-022-01490-1
Citation  Mealer RG, et al. (2022) The schizophrenia-associated variant in SLC39A8 alters protein glycosylation in the mouse brain. Mol Psychiatry 27(3):1405-1415
abstractText  A missense mutation (A391T) in SLC39A8 is strongly associated with schizophrenia in genomic studies, though the molecular connection to the brain is unknown. Human carriers of A391T have reduced serum manganese, altered plasma glycosylation, and brain MRI changes consistent with altered metal transport. Here, using a knock-in mouse model homozygous for A391T, we show that the schizophrenia-associated variant changes protein glycosylation in the brain. Glycosylation of Asn residues in glycoproteins (N-glycosylation) was most significantly impaired, with effects differing between regions. RNAseq analysis showed negligible regional variation, consistent with changes in the activity of glycosylation enzymes rather than gene expression. Finally, nearly one-third of detected glycoproteins were differentially N-glycosylated in the cortex, including members of several pathways previously implicated in schizophrenia, such as cell adhesion molecules and neurotransmitter receptors that are expressed across all cell types. These findings provide a mechanistic link between a risk allele and potentially reversible biochemical changes in the brain, furthering our molecular understanding of the pathophysiology of schizophrenia and a novel opportunity for therapeutic development.
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