# Synaptic dysglycosylation caused by the schizophrenia-risk variant in SLC39A8

> **NIH NIH K08** · OREGON HEALTH & SCIENCE UNIVERSITY · 2022 · $195,771

## Abstract

PROJECT SUMMARY/ABSTRACT
Schizophrenia is a severe mental illness with strong heritability, and advances in genetics have started to
unravel the complex molecular underpinnings of this disorder. GWAS have identified over 250 loci linked to
schizophrenia which are enriched near genes expressed in CNS neurons and involved in synaptic biology.
Most schizophrenia-associated variants are in the non-coding region of the genome, though a small number
result in a mutation within a known protein. The most significantly associated coding variant in schizophrenia
GWAS is rs13107325 in SLC39A8, resulting in a missense mutation (A391T) in the eponymous manganese
(Mn2+) transporter. Mn2+ transport by SLC39A8 is critical for glycosylation, the enzymatic attachment of
carbohydrates to proteins and lipids, which is involved in neurodevelopment and synaptic function.
Here, the applicant will investigate a novel molecular mechanism underlying increased schizophrenia risk in
A391T carriers using a mouse model of genetic risk. Having shown that A391T mice have altered glycosylation
of synaptic proteins, including neurotransmitter receptors and cell adhesion molecules, the applicant will test if
altered glycosylation of these proteins changes their trafficking and localization, deposition of complement, and
the number of dendritic spines in the frontal cortex (Aim 1). Next, he will attempt to reverse previously identified
glycome changes with oral Mn2+ supplementation, overcoming impaired SLC39A8 transport from A391T.
These studies will employ existing genetically engineered mouse lines, glycobiology techniques pioneered by
the applicant, and cutting-edge neuroscience training in analysis of the synapse. Together, these aims will
define the molecular alterations caused by A391T at the synapse and provide critical preclinical data for Mn2+
supplementation in carriers of A391T during critical periods of brain development and maturation.
The applicant, Dr. Robert Mealer, is well qualified to execute the proposed experiments with his background in
neuroscience, psychiatric genetics, and glycobiology. The four-year training plan will foster development
towards independent investigator status and generate the preliminary data necessary for a future R01
application with clear therapeutic potential. He will continue his mentee relationships with Drs. Smoller and
Cummings, while receiving additional training and mentorship from Dr. Morgan Sheng on the molecular
analysis of the synapse. He has also enlisted Dr. Michael Aschner, a world leader on Mn2+ in the brain, and Dr.
Maurizio Fava, a clinician researcher with extensive experience in psychopharmacology and trial design, as
members of his research advisory committee. Finally, the collaborative research environment is ideal for
furthering the applicant’s goal of becoming an independent researcher in academic psychiatry.

## Key facts

- **NIH application ID:** 10694488
- **Project number:** 7K08MH128712-03
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Robert G Mealer
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $195,771
- **Award type:** 7
- **Project period:** 2023-01-31 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10694488

## Citation

> US National Institutes of Health, RePORTER application 10694488, Synaptic dysglycosylation caused by the schizophrenia-risk variant in SLC39A8 (7K08MH128712-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10694488. Licensed CC0.

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