# Characterization of a Novel Mutation Associated with Vacuolar Tauopathy

> **NIH NIH F30** · UNIVERSITY OF PENNSYLVANIA · 2020 · $32,587

## Abstract

Project Summary/Abstract
 Our long term goal is to understand the pathogenesis of a novel neurodegenerative disease in a family
harboring a previously undescribed mutation. This family is afflicted with frontotemporal dementia (FTD),
inherited in an autosomal dominant pattern. The neuropathology associated with this mutation is comprised of
cytoplasmic vacuolization of neocortical neurons and Alzheimer’s disease-like tau protein aggregation. This
pathology differs from any pathology described in the literature. Furthermore, this mutation represents the only
FTD causing mutation associated with tau pathology outside of mutations in the tau gene itself. The first step in
understanding the pathogenesis of this novel neurodegenerative disease is to understand the biochemical
effect of this mutation. We hypothesize that this mutation disrupts critical protein structure leading to protein
loss-of-function. Specific Aim 1 will determine the biochemical structure of this mutant protein. We will use a
combination of computational modeling and fluorometric imaging to understand how this mutation differs from
wild type and other disease associated mutants of this protein. Specific Aim 2 will determine the biochemical
function of this mutant protein. We will use biochemical assays to characterize the enzymatic activity, substrate
binding profile, and interaction with pathologic tau fibrils. Through our studies, we will begin to understand the
pathogenesis of this novel neurodegenerative disease and gain insight on a new mechanism for Alzheimer’s
disease pathology.

## Key facts

- **NIH application ID:** 9830532
- **Project number:** 5F30AG058317-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Nabil Darwich
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $32,587
- **Award type:** 5
- **Project period:** 2017-12-01 → 2020-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9830532

## Citation

> US National Institutes of Health, RePORTER application 9830532, Characterization of a Novel Mutation Associated with Vacuolar Tauopathy (5F30AG058317-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9830532. Licensed CC0.

---

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