# Project 1: Identifying genes and Pathways that impact Tau Toxicity in FTD

> **NIH NIH U54** · MAYO CLINIC  JACKSONVILLE · 2020 · $459,423

## Abstract

PROJECT SUMMARY/ABSTRACT
Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are Parkinsonian disorders with
predominant tau pathology at autopsy. A common non-recombining haplotype at the microtubule associated
protein tau gene (MAPT) locus on chromosome 17q21 increases the risk of PSP and CBD and recently our
genome-wide association efforts identified variation in additional genes/loci (STX6, EIF2AK3, SOS1, KIF13B,
and MOBP/Appoptosin). In addition, other genes, as yet undetected, likely contribute to susceptibility to PSP
and CBD. This study aims to resolve the disease-associated genetic variation within the exome and whole
genome sequence data from PSP and CBD patients, to determine the pathological consequences and
mechanisms underlying these complex neurodegenerative diseases characterized by tau pathology, thus
identifying potential therapeutic targets. For Aim 1, we will analyze a unique dataset consisting of over 600
exomes and 2400 whole genome sequences derived from pathology-confirmed PSP patients and 350 exomes
from CBD patients. These data will be compared to the 5000 control exomes available through the Alzheimer's
sequencing project for single nucleotide variant (SNV) analysis. In Aim 2, we will expand our analysis of this
cohort and specifically analyze structural variants (SV) and copy number variations (CNV) that contribute to
PSP and CBD using a range of analytical software programs which we have extensively tested to achieve
optimal sensitivity for each type of variation. For Aim 3, we will use the available exome and whole genome
sequence data to assess the association of genetic variation on tau toxicity and pathology with Core C, by
assessing tau burden in different brain regions and microgliosis as a surrogate of neuronal cell loss. On-going
efforts have shown that using quantitative pathologic measures can help distinguish subtypes of PSP. For Aim
4, we will determine the effect of significantly associated variants/genes identified. We will examine mRNA
expression, RNA-Seq data, in vitro functional studies to characterize the effect of the observed mutation on tau
aggregation and microtubule assembly, and the effect of these genes/variants on tau protein levels and
isoforms in postmortem brain tissue. In summary, the combination of whole exome and whole genome
sequence data from pathologically-confirmed and highly-phenotyped patients with an in-depth analytical plan
focusing on SNV, CNV, SV and quantitative traits, provides a unique opportunity for novel gene discovery.
Identifying novel genes for tauopathies is a critical step towards a better understanding of the
pathomechanisms underlying this group of disorders and may help identify prognostic biomarkers for these
devastating disorders.

## Key facts

- **NIH application ID:** 10012956
- **Project number:** 5U54NS100693-05
- **Recipient organization:** MAYO CLINIC  JACKSONVILLE
- **Principal Investigator:** GERARD DAVID SCHELLENBERG
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $459,423
- **Award type:** 5
- **Project period:** 2016-09-30 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10012956

## Citation

> US National Institutes of Health, RePORTER application 10012956, Project 1: Identifying genes and Pathways that impact Tau Toxicity in FTD (5U54NS100693-05). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10012956. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*