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The schizophrenia-associated variant in SLC39A8 alters N-glycosylation of critical proteins in the mouse brain

ABSTRACT: A missense mutation (A391T) in the manganese transporter SLC39A8 is strongly associated with schizophrenia through GWAS, though the molecular connection to the brain remains hypothetical. Human carriers of A391T have reduced serum manganese, altered plasma glycosylation, and brain MRI changes consistent with altered metal transport. Here, using a mouse knock-in model homozygous for A391T, we show that the schizophrenia-associated variant changes protein glycosylation in the brain. N-linked glycosylation was most significantly impaired, with effects differing between regions. RNAseq analysis showed negligible variation, consistent with changes in the activity of glycosylation enzymes rather than gene expression. Finally, one third of all 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. These findings provide a mechanistic link between a risk allele and biochemical changes in the brain, furthering our molecular understanding of the pathophysiology of schizophrenia.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Christina Woo

LAB HEAD: Christina Woo

PROVIDER: PXD021632 | Pride | 2022-03-08

REPOSITORIES: Pride

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			Action	DRS
	190823L_SAM05765_BY17_1.raw	Raw
	190823L_SAM05765_BY17_10.raw	Raw
	190823L_SAM05765_BY17_11.raw	Raw
	190823L_SAM05765_BY17_12.raw	Raw
	190823L_SAM05765_BY17_13.raw	Raw

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