# Defining TBK1-associated autophagy networks in neurons

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $789,130

## Abstract

Project Summary/Abstract
Frontotemporal dementia (FTD) is characterized by the unrelenting loss of cortical neurons that manifests
clinically as devastating changes in the behavior, language, and personality of affected individuals.
Amyotrophic lateral sclerosis (ALS) is a related neurodegenerative disease that results in rapidly progressive
motor deficits and eventual paralysis. Disease-modifying treatments for FTD and ALS remain elusive. Loss of
function variants in TBK1, which encodes a multifunctional protein kinase, represent one of the most common
genetic causes of FTD, ALS, and combined ALS/FTD. TBK1 has been implicated in innate immunity,
apoptosis, neuroinflammation, and autophagy. One of its key substrates is optineurin (OPTN), which functions
in selective autophagy, and haploinsufficiency of OPTN has been strongly linked to familial ALS/FTD. This
suggests that disruption of selective autophagy, which acts to maintain protein homeostasis and organelle
quality control, is sufficient to cause neurodegeneration. However, selective autophagy has not been well-
characterized in neurons and how reduced TBK1 activity leads to the loss of excitatory neurons remains
unclear. Our preliminary efforts to systematically evaluate the effects of TBK1 loss-of-function, including
unbiased phospho-proteomics, indicate that TBK1 regulates the phosphorylation of numerous proteins
involved in autophagy and lysosomal pathways. Additionally, we have identified interactions between OPTN
and specific organelles. Our central hypothesis is that TBK1 controls OPTN and additional selective
autophagy cargo receptors to target proteins and organelles for degradation and maintain neural proteostasis.
The overall objective of this proposal is to integrate new stem cell-based models of ALS/FTD with advanced
proteomics for a comprehensive understanding of TBK1-associated autophagy pathways in human neurons.
In this proposal we aim to: 1) Identify novel TBK1 protein substrates in human stem-cell derived neurons and
characterize the effects of TBK1 loss on neural regeneration; 2) Define the consequences of OPTN loss and
disease-associated variants in autophagy; 3) Construct selective autophagy cargo receptor protein-protein
interaction networks in neurons and assess their contributions to a form of secretory autophagy. Our long-
term goal is to better understand selective autophagy to support the development of novel targeted
therapeutic approaches to modulate this pathway in age-related neurodegeneration.

## Key facts

- **NIH application ID:** 10985587
- **Project number:** 1R01AG089849-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Daniel Adam Mordes
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $789,130
- **Award type:** 1
- **Project period:** 2024-08-15 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10985587

## Citation

> US National Institutes of Health, RePORTER application 10985587, Defining TBK1-associated autophagy networks in neurons (1R01AG089849-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10985587. Licensed CC0.

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