# Molecular Genetic Analysis of TORC1 and TORC2 Signaling in Neuronal Maintenance

> **NIH NIH R01** · STANFORD UNIVERSITY · 2020 · $342,344

## Abstract

Project Summary
Age-related neurodegenerative diseases such as Parkinson's disease (PD) impose tremendous socioeconomic
burdens due to the lack of disease-modifying treatment options. Mitochondrial dysfunction is intimately linked to
neurodegenerative diseases. How mitochondrial abnormalities arise and how they relate to other features of
neurodegenerative diseases such as proteostasis failure, Ca2+ dyshomeostasis, and neuroinflammation are poorly
understood. Dynamic control of the structure, function, and distribution of mitochondria is also essential for normal
neuronal function, a requirement necessitated by the highly polarized shape and unique physiology of neurons.
Despite intensive efforts, many fundamental questions remain regarding the mechanisms linking mitochondrial
regulation to neuronal maintenance. Pten-induced kinase 1(PINK1) and Parkin (encoding an E3 ubiquitin ligase),
two genes associated with familial PD, have defined a genetic pathway important for mitochondrial and neuronal
maintenance in flies and mammals. Identification of this pathway offers a much-needed entry point to understand
the regulation of mitochondrial function in response to neuronal activity and metabolic needs, and to decipher the
mechanistic link between mitochondrial dysfunction and other pathological hallmarks of disease. Our genetic studies
revealed that PINK1/Parkin directs an interconnected mitochondrial quality control (MQC) process important for the
maintenance of dopaminergic (DA) neurons. The multifaceted MQC process encompasses translational control of
respiratory chain complex (RCC) biogenesis, mitochondrial fission/fusion dynamics, transport, and removal of
defective mitochondria by autophagy (mitophagy). In the past funding period we have shown that the conserved
target of rapamycin complexes (TORC1 and TORC2) act as important mediators of PINK1-directed MQC. One
exciting finding from our investigation is that the PINK1/mTORC2 pathway exerts translational control of nuclear
encoded RCC (nRCC) mRNAs. The goal of this proposal is to move away from the status quo of mitophagy-centric
focus of PINK1-directed MQC by focusing on the newly discovered translational control function of PINK1/mTORC2
signaling. We will use a unique combination of molecular genetic, genomic, cell biological, and biochemical tools,
and move between in vivo fly models and in vitro induced DA neuron (iDN) models. Our central hypothesis is that
PINK1/mTORC2 signaling regulates DA neuron function and survival through ribosome-associated co-translational
quality control (RQC) of select nuclear-encoded mitochondrial mRNAs, thus mechanistically linking mitochondrial
function to protein homeostasis. We propose to elucidate how the RQC pathway mediates the effects of
PINK1/mTORC2 on mitochondrial regulation and DA neuron maintenance (Aim 1), and dissect the molecular
mechanism of RQC regulation by PINK1/mTORC2 signaling in both Drosophila models and patient-derived iDN
models (Aim 2)....

## Key facts

- **NIH application ID:** 9903463
- **Project number:** 5R01NS084412-07
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Bingwei Lu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $342,344
- **Award type:** 5
- **Project period:** 2013-12-15 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9903463

## Citation

> US National Institutes of Health, RePORTER application 9903463, Molecular Genetic Analysis of TORC1 and TORC2 Signaling in Neuronal Maintenance (5R01NS084412-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9903463. Licensed CC0.

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