# Project 1: Aberrant neuronal activity and tau distribution in FTD

> **NIH NIH U54** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $345,495

## Abstract

ABSTRACT — PROJECT 1
FTLD-tau exhibits imbalanced tau proteostasis (intra- and inter-cellar) and neuronal dysfunction. However, little
is known about how the accumulation and spread of pathogenic tau could occur, and how it could affect
neuronal and synaptic functions. As an integral part of the Center, project 1 (P1)'s objective is to dissect
mechanisms underlying aberrant neuronal activity and tau distribution in FTD. We combine unbiased
and hypothesis-driven approaches, which are extremely powerful but cannot be achieved without the structure
of the Center. We propose three Specific Aims. In Aim 1, we will define FTD mutations-induced aberrant tau
post-translational modifications (PTMs) and dissect how acetylation stimulates tau release with P3. Aim 1 will
also be complemented by transcriptome analyses of the FTD mutation effects in P2. In Aim 2, we will
determine how FTLD-tau alters neuronal activity and activity-dependent tau release. We will expand on our
preliminary study that V337M human neurons exhibit hyperexcitability with impaired homeostatic regulation of
axon initial segment (AIS). We will systematically compare neuronal and synaptic activity in isogenic FTD
mutant and control lines by whole-cell recordings. Working with mass-spec (MS) core, we will also dissect the
mechanism underlying the activity-dependent tau release by dissecting tau interactome in response to high
KCL (MS core). CRISPRi/a will then be performed to examine how modulating hits from interactome study
would affect activity-dependent tau release (CRISPR core). Aim 2 in P1 will be complemented by P2, which
correlates neuronal activity with transcriptome, and P3, which examines the crosstalk between neuronal
activity and tau degradation pathways. In Aim 3, we will determine how FTD mutations affect pathogenic tau
seeding. Pathogenic seeding is a key feature in tauopathy, but little is known about its mechanisms and
functional outcome. We will compare neuronal and synaptic activity in receiving human neurons positive or
negative for FRET signal resulting from tau oligomerization. To dissect the mechanisms mediating pathogenic
seeding, we will compare the proteome associated with internalized mutant or WT tau seeds in human neurons
(MS core). Proteins selectively linked with mutant tau will be prioritized as potential hits. Working with CRISPR
core, we will inhibit/activate selected genes from the seeding proteome, and measure the outcome by FRET
signal and whole-cell recordings. The proteomic approach in Aim 3 will be complemented by the genome-wide
screening to identify pathways in internalization using unbiased approach (P2 and CRISPR core). Together
with P2 and P3, P1 will contribute to our overall vision of dissecting the crosstalk between tau proteostasis
imbalance and neuronal dysfunction.

## Key facts

- **NIH application ID:** 10011932
- **Project number:** 5U54NS100717-05
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Li Gan
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $345,495
- **Award type:** 5
- **Project period:** 2016-09-30 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10011932

## Citation

> US National Institutes of Health, RePORTER application 10011932, Project 1: Aberrant neuronal activity and tau distribution in FTD (5U54NS100717-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10011932. Licensed CC0.

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