# TBCK Encephaloneuronopathy: establishing the role of mitochondrial dysfunction in promoting neurodegeneration

> **NIH NIH K02** · CHILDREN'S HOSP OF PHILADELPHIA · 2021 · $191,894

## Abstract

PROJECT SUMMARY
Autosomal recessive mutations in the TBCK gene cause intellectual disability of variable severity. I have
further characterized the neurologic phenotype of Puerto Rican children with a homozygous null mutation
(p.R126X) in TBCK, which we designated the Boricua mutation. The biological mechanism underlying the
genotype-phenotype correlations remain unclear. On one extreme, patients with the severe Boricua mutation
develop progressive brain, cerebellar and motor neuron atrophy, coarse facial features and epilepsy. We
named this severe syndrome TBCK-encephaloneuronopathy (TBCKE). On the other hand, other patients with
biallelic TBCK mutations have clinical diagnosis of autism and/or intellectual disability, without evidence of
neurodegeneration. The function of TBCK protein is unknown, but previous studies have shown absence of
TBCK leads to downregulation of mTORC1 signaling. The mTORC1 pathway regulates autophagy, including
the targeted degradation of mitochondria (mitophagy). I recently reported increased autophagic flux and
impaired glycoprotein degradation in TBCKE patients’ fibroblasts, which was rescued by activating mTORC1
signaling with L-leucine. Our fibroblasts studies suggests that TBCKE patients have mitochondrial dysfunction
and mitochondrial DNA (mtDNA) depletion. Furthermore, the degree of mtDNA depletion predicts the
neurologic severity of TBCK disease. Therefore, I hypothesize that loss of function of TBCK in human neurons
leads to mtDNA depletion and mitochondrial dysfunction due to excessive autophagic clearance of
mitochondria. To test this hypothesis in more disease relevant models, I propose to generate TBCK-null
induced pluripotent stem cell (iPSC) derived neurons (iNeu) and tbck-/- zebrafish. The goal of this proposal is to
address whether loss of function of TBCK affects mitochondrial function in human neurons, and to
determine whether mtDNA depletion modulates the severity of neurodegeneration in TBCK disease.
Using novel disease models and unique tools to assay mitochondrial function, I propose to address the
following questions: (Aim 1) Do human neurons lacking TBCK protein have excessive mitophagy? (Aim2)
What is the function of TBCK? Can we define its protein-protein interactions in neurons? (Aim 3) Can TBCK-
null zebrafish model the variable severity of TBCK disease? Can mtDNA depletion modulate the severity of the
phenotype in vivo? The experiments outlined in this proposal will determine the role of mitochondria in TBCKE
and whether mtDNA depletion is sufficient to drive the neurodegenerative phenotype or merely an
epiphenomenon. This work will also provide training in novel techniques for assaying neuronal mitochondrial
function in disease models in situ. I will also learn to develop and characterize zebrafish models of
neurodevelopmental disease. Support from this K02 award will be instrumental in growing my independent
research program as a physician scientist in a superb institutional environment...

## Key facts

- **NIH application ID:** 10141310
- **Project number:** 5K02NS112456-02
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** XILMA R ORTIZ-GONZALEZ
- **Activity code:** K02 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $191,894
- **Award type:** 5
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10141310

## Citation

> US National Institutes of Health, RePORTER application 10141310, TBCK Encephaloneuronopathy: establishing the role of mitochondrial dysfunction in promoting neurodegeneration (5K02NS112456-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10141310. Licensed CC0.

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