# TBK1 and mitochondrial dysfunction in frontotemporal dementia

> **NIH NIH R03** · CASE WESTERN RESERVE UNIVERSITY · 2020 · $161,000

## Abstract

ABSTRACT
Frontotemporal dementia (FTD) is the second most common form of dementia in patients under the age of 65
years. FTD is characterized by atrophy of the frontal and temporal lobes of the brain, personality changes and
language impairment. FTD also shares some of the same genetic features as amyotrophic lateral sclerosis
(ALS). Genetic advances have identified mutations in more than a dozen genes which can cause pure FTD,
pure ALS or both. However, how these genetic mutations contribute to the pathogenesis of FTD remain to be
characterized. Significant to this proposal, one gene found mutated in both disorders is the TANK binding
protein 1 (Tbk1). Previous studies suggest that haploinsufficiency of TBK1 (reduced TBK1protein levels) is
causative for FTD and ALS. TBK1 is a multifunctional kinase which can phosphorylate a variety of substrates
in order to exert its functions in a few cellular processes including innate immune system. However, our
understanding of the physiological functions of TBK1 in neurons and how the loss of TBK1 contributes to
neurodegeneration remains limited. To generate preliminary data, we used Tbk1 shRNA to knock down Tbk1
gene expression in rat primary neurons and explore neuronal functions of TBK1. We also used the CRISPR
technique to generate human TBK1 knockout induced pluripotent stem cells (iPSC), and differentiated them
into cortical-like neurons, one cell type affected in FTD. In both types of neurons, we found that TBK1 reduction
impairs mitochondrial dynamics and causes mitochondrial fragmentation. By analyzing proteomic data, we
found a cluster of TBK1 interacting proteins related to mitochondria. One of these is the mitochondria fusion
protien OPA1, related to mitochondrial dynamics. Our further studies demonstrated that: 1) TBK1 is localized
on and co-purifies with pure mitochondria; 2) Permeabilization and digestion assays suggested that a portion
of TBK1 can locate inside of mitochondria as TBK1 is more resistant to digestion than the mitochondrial outer
membrane protein TOM20; 3) TBK1 proteomic data demonstrated that TBK1 physically interacts with
mitochondria import proteins such as TOM70, TIM50 and TIM44; 4) OPA1 immunoprecipitation also pulls
down TBK1, and OPA1 has predicted phosphorylation sites by TBK1; 6) TBK1 reduction also impairs OPA1
processing in both type of neurons; 7) TBK1 reduction decreases the mitochondrial membrane potential and
causes an abnormal dendritic spine phenotype. Based on these exciting preliminary studies, we hypothesize
that TBK1 plays an important role in controlling mitochondrial dynamics and function through the
interaction with OPA1, and the loss of TBK1-OPA1 interaction causes mitochondrial and neuronal
dysfunction. Our proposed study will be the first mechanistic study investigating the effect of TBK1 reduction
on mitochondrial dynamics/function and neuronal function, and will likely reveal a novel role of TBK1 in the
regulation of mitochondrial dynamics/function....

## Key facts

- **NIH application ID:** 10109793
- **Project number:** 1R03NS120064-01
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Yubing Lu
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $161,000
- **Award type:** 1
- **Project period:** 2020-09-30 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10109793

## Citation

> US National Institutes of Health, RePORTER application 10109793, TBK1 and mitochondrial dysfunction in frontotemporal dementia (1R03NS120064-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10109793. Licensed CC0.

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