The brain contains a multitude of glycoproteins modified with glycans on multiple amino acids, including N-glycans and O-glycans, but the functions and structures of the glycans and all sites of glycosylation on proteins is not yet well defined. Our analyses are revealing that the assortment of the major N-glycans in the brain glycoproteins of mice and humans have a remarkable enrichment of relatively small-sized glycans, including pauci- and oligomannose, hybrid-type, and complex-type lacking extensive galactosylation or sialylation, despite the overall repertoire of glycans being relatively robust. All of these results are consistent with transcriptomic analyses of murine and human brains. Many human psychiatric and brain disorders, including schizophrenia and Alzheimer’s Disease (AD) may be linked to changes in protein glycosylation.
In our studies on schizophrenia, we have focused on a missense mutation (A391T) in SLC39A8, encoding a manganese-transporter, that is strongly associated with schizophrenia in genomic studies, though the molecular connection to the brain is unknown. We have investigated brain glycosylation in a knock-in mouse model homozygous for A391T, and found that there are significant changes in protein N-glycosylation in the brain, also associated with changes in glycoprotein expression.
In Alzheimer’s disease patients, along with brain samples from asymptomatic and normal controls, we have analyzed the overall glycoproteome, identifying many hundreds of different glycoproteins and sites of glycosylation, and identified significant changes in N-glycosylation patterns that differ from normal and asymptomatics. Our studies are revealing mechanistic links between a risk allele and potentially reversible biochemical changes in the schizophrenic brain, furthering our molecular understanding of the pathophysiology of schizophrenia and a novel opportunity for therapeutic development. Also, the new information on brain glycoproteome in AD may provide new biomarkers of disease and effects of modern therapeutic interventions.