# Cell Death Regulation by Pro-Apoptotic BOK in Tauopathies

> **NIH NIH RF1** · YALE UNIVERSITY · 2024 · $1,969,620

## Abstract

PROJECT SUMMARY
Alzheimer's disease (AD), and other neurodegenerative tauopathies, are defined by their pathologic
accumulation of overexpressed, hyperphosphorylated, and oligomerized tau. Tau tangles result in proteotoxic
stress through the endoplasmic reticulum (ER), cell death, and ultimately neurodegeneration. Understanding the
molecular mechanisms that lead from tau aggregation to neuron loss is key to identify novel therapeutic targets.
We have elucidated how the BCL-2 family member BOK induces apoptosis in response to ER stress stimuli.
Specifically, we have found that BOK, which is predominantly bound to the inositol-3-phosphate (IP3R) calcium
transporter in the ER, regulates the unfolded protein response (UPR) as well as the transfer of calcium from the
ER to the mitochondria. Critically, BOK plays an important role in the formation of mitochondrial-ER contact sites
(MERCs), also known as mitochondrial ER-associated membranes (MAMs). MAMs are central signaling hubs
for the cell, mediating processes like calcium transfer, the UPR, mitochondrial shape and metabolic homeostasis.
Neurodegenerative diseases have been associated with the abnormal quantity, formation and function of MAMs.
In preliminary work we find that BOK regulates metabolic survival and cell death pathways in neurons. Our goal
is to determine how the control of metabolic pathways through MAMs by BOK regulates neuronal cell death due
to tau. Aim 1 will examine how BOK regulates tau-induced neuronal cell death through its regulation of ER to
mitochondrial calcium transfer. Aim 2 will determine how BOK impacts autophagy through MAMs and its
consequences for tauopathy. Aim 3 will define the ability of BOK to control lipid metabolism in tau-bearing
neurons. Each of these aims focuses on metabolic pathways that signal through MAMs, that are known to be
important for AD, and for which we have preliminary data implicating a role for BOK. This project will benefit from
a multidisciplinary approach that includes neuronal genetic reprogramming, cutting-edge intravital microscopy,
and advanced lipidomics. We will employ 2Phatal, two-photon chemical apoptotic targeted ablation, a novel
technique we developed to induce and measure cell death in live mammalian brains without neighboring injury.
These novel tools will enable us to address our conceptually innovative hypothesis that tauopathy-induced
neuronal cell death is regulated by BOK's control of metabolic pathways that signal through MAMs. Discernment
of the signaling networks that control the balance between metabolic homeostasis and cell death during tau-
induced neurodegeneration is expected to provide targets for therapeutic development.

## Key facts

- **NIH application ID:** 10978687
- **Project number:** 1RF1NS126251-01A1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Samuel G Katz
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,969,620
- **Award type:** 1
- **Project period:** 2024-09-17 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10978687

## Citation

> US National Institutes of Health, RePORTER application 10978687, Cell Death Regulation by Pro-Apoptotic BOK in Tauopathies (1RF1NS126251-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10978687. Licensed CC0.

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