# Targeting Tau Proteoforms in Frontotemporal Dementia

> **NIH NIH RF1** · WASHINGTON UNIVERSITY · 2021 · $1,815,043

## Abstract

Tauopathies may occur by familial mechanisms in which mutations in the MAPT gene are dominantly
inherited causing frontotemporal lobar degeneration (FTLD-tau) or by sporadic mechanisms in which MAPT
haplotypes are associated with increased disease risk (e.g. progressive supranuclear palsy and corticobasal
degeneration). MAPT mutations and risk haplotypes have been proposed to drive disease pathogenesis
through proteoforms that contain 3-microtubue binding domain repeats (3R tau), 4R tau, or both. However, the
mechanisms by which tauopathies occur remains poorly understood. We propose that MAPT mutations drive
tau aggregation and neuronal dysfunction through altered proteostasis. In preliminary studies, we have shown
that induced pluripotent stem cell derived-neurons expressing MAPT mutations exhibit changes in tau turnover
compared to isogenic, control neurons, and we observed differences in the turnover of specific tau proteoforms
in mutant neurons. Neurons expressing MAPT mutations exhibit enlarged lysosomal structures and secondary
elevation of lysosomal enzymes, markers of lysosomes that are unable to properly degrade their contents.
Correction of the mutant allele was sufficient to restore these lysosomal defects. This suggests that altered tau
kinetics may be due to defects in the endolysosomal pathway. Thus, a unifying feature by which MAPT
mutations drive tauopathy is through disrupted proteostasis. The objective of this study is to extend our
preliminary findings to manipulate tau proteoforms using genetic or molecular methods to define the
mechanisms by which tau proteoforms disrupt proteostasis in tauopathies. We hypothesize that tau
proteoforms are sufficient to destabilize proteostasis and to result in the accumulation of tau in vulnerable brain
regions. To test this hypothesis, we will determine the extent to which MAPT mutations cause impaired tau
phenotypes and proteostasis characteristic of tauopathy. We will also generate a systematic genetic interaction
map to elucidate connections between MAPT mutations, proteostasis, and associated therapeutic targets.
Together, this study will reveal novel mechanisms underlying tauopathy that are driven by specific tau
proteoforms and whether therapeutics designed to block specific tau proteoforms impact pathologic events.

## Key facts

- **NIH application ID:** 10306108
- **Project number:** 1RF1NS110890-01A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Celeste Marie Karch
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,815,043
- **Award type:** 1
- **Project period:** 2021-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10306108

## Citation

> US National Institutes of Health, RePORTER application 10306108, Targeting Tau Proteoforms in Frontotemporal Dementia (1RF1NS110890-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10306108. Licensed CC0.

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