# Involvement of an ER to lysosome signaling axis in the onset of neurodegeneration in models of AD

> **NIH NIH R21** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2020 · $421,329

## Abstract

SUMMARY
Accumulation of neurofibrillary tangles comprised of Tau, or mutations in the gene encoding this protein, are
common in Alzheimer’s disease (AD) and related dementias such as frontotemporal dementia (FTD). Tau
contributes to neurodegeneration via two related pathways. First, Tau forms aggregates that are toxic to neurons.
Autophagy and lysosomal degradation are of particular interest when considering the removal of Tau aggregates.
The idea here is that potentiation of autophagy and lysosomal degradation would rid the cells of aggregates, and
thus, alleviate neurotoxicity. Second, at a cellular level, Tau perturbs several key aspects of neuronal function.
Studies have shown that mutant Tau can lead to Ca2+ dyshomeostasis, perturbations in neuronal excitability and
bioenergetics, and alterations in transcriptional and translational programs. The overarching goal of our
exploratory grant application is to bridge these two concepts. We built the aims of this project on the basis of
preliminary studies that demonstrate the onset of severe lethality upon expression of human tau or tauR406W in
Drosophila glutamatergic neurons. We propose the involvement of two distinct modules of Ca2+ dyshomeostasis
working in sequence to impart dysfunction. The first involves elevated inositol trisphosphate (IP3) production and
IP3 receptor (IP3R)-mediated ER Ca2+ release. The Ca2+ coming out of the ER is loaded into endolysosomes,
and subsequent release of vesicular Ca2+ through the TRPML endolysosomal Ca2+ release channels leads to
decline in animal viability. In support of this model, knockdown of genes encoding IP3R or TRPML almost
completely prevented the lethality stemming from either Tau or TauR406W. Furthermore, epistasis analyses place
TRPML downstream of IP3R in the sequence of events leading to neurotoxicity. In this application, we propose
three specific aims to delineate the mechanisms underlying these intriguing findings. In Aim 1, we will determine
the cell biological correlates of IP3R- and TRPML-dependent decline of organismal viability. We will test the
hypothesis that neuronal cell death imposed by Tau or TauR406W are either delayed or prevented by the genetic
attenuation of the IP3R–TRPML axis. In Aim 2, we will test the hypothesis that Ca2+ released by IP3Rs is
sequestered into endolysosomes. Thus, we will determine whether IP3R hyperactivation in neurons expressing
tau variants leads to an increase in endolysosomal Ca2+ content and elevated TRPML activity. Finally, in Aim 3,
we seek to elucidate the mechanisms linking TRPML-mediated endolysosomal Ca2+ release with neurotoxicity.
Successful completion of these aims would point to the critical involvement of an IP3R–TRPML axis in
neurotoxicity resulting from Tau variants, and motivate future studies designed to evaluate the conservation of
these pathways in mouse models of AD and FTD.

## Key facts

- **NIH application ID:** 9969856
- **Project number:** 1R21AG067414-01
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** KARTIK VENKATACHALAM
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $421,329
- **Award type:** 1
- **Project period:** 2020-05-15 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9969856

## Citation

> US National Institutes of Health, RePORTER application 9969856, Involvement of an ER to lysosome signaling axis in the onset of neurodegeneration in models of AD (1R21AG067414-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9969856. Licensed CC0.

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