# Functional evaluation of genes adjacent to risk-modulating SNPs in the pathogenesis of PSP

> **NIH NIH R21** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $434,125

## Abstract

Progressive supranuclear palsy (PSP) is a neurodegenerative disease characterized clinically by motor, cognitive
an oculomotor deficits and pathologically by neuronal loss, microgliosis, and accumulation of insoluble deposits
of the 4-repeat isoform of the microtubule-associated protein Tau (4R-Tau). Current management only
addresses symptoms and there is an urgent need for effective treatments that prevent disease progression.
Genetic evidence firmly implicates Tau in pathogenesis, although the mechanisms resulting in tauopathy and
neuronal loss are unknown. Genome-wide association studies (GWAS) have identified PSP-associated single
nucleotide polymorphisms (SNPs) that are associated with functional changes in adjacent genes. The risk allele
of a SNP within STX6 is associated with decreased STX6 expression. The risk allele of a SNP in MOBP is
associated with increased expression of a neighboring gene, SLC25A38. The risk allele of a SNP in EIF2AK3 is in
linkage disequilibrium with non-synonymous coding variants that impair the function of the protein. Since the
products of these three genes do not converge on a single cellular function, it is likely they each contribute to a
different component of PSP pathogenesis, which encompasses multiple neuron-intrinsic and cell non-
autonomous events. Consequently, we hypothesize that: genes influenced by PSP-associated SNPs each
contribute to distinct and specific mechanisms mediating the pathogenesis of tauopathy in vivo. Key features
of PSP pathogenesis are not easily replicated in vitro, so it would be desirable to test this hypothesis in vivo.
However, this is a daunting task given the growing list of PSP-linked SNPs. In order to address this roadblock,
we developed a novel zebrafish model of PSP that is optimized for rapid evaluation of genetic modifiers.
Transgenic zebrafish expressing human 4R-Tau replicate key features of PSP, including neurological deficits,
neurodegeneration, neuroinflammation and tauopathy. In this exploratory proposal, we will test the utility of
this model for determining how genes adjacent to PSP-associated SNPs influence the pathogenesis of tauopathy
in vivo. We have identified conserved zebrafish homologs of STX6, SLC25A38 and EIF2AK3, and generated an
allelic series of mutations using CRISPR-Cas9 mutagenesis. By crossing these new mutant alleles with our
zebrafish PSP model, we will determine how changes in the expression of these three genes alter: survival, motor
and oculomotor abnormalities (aim 1); neuroinflammation, synapse loss, oxidative stress, and neuronal cell
death (aim 2); and Tau expression, phosphorylation, truncation, aggregation and mislocalization (aim 3) in vivo.
We will employ unbiased, automated, and quantitative phenotyping tools, statistically robust samples, and
multiple biological replicates, to enhance rigor and reproducibility. Together, these data will elucidate distinct
roles for STX6, EIF2AK3 and SLC25A38 in tauopathy. Importantly, this study ...

## Key facts

- **NIH application ID:** 10285679
- **Project number:** 1R21NS123211-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Edward Alan Burton
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $434,125
- **Award type:** 1
- **Project period:** 2021-07-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10285679

## Citation

> US National Institutes of Health, RePORTER application 10285679, Functional evaluation of genes adjacent to risk-modulating SNPs in the pathogenesis of PSP (1R21NS123211-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10285679. Licensed CC0.

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