# Regulation of Dendrite Homeostasis by PINK1 and PKA in Models of Parkinson's Disease

> **NIH NIH R01** · UNIVERSITY OF NEVADA RENO · 2020 · $313,272

## Abstract

PROJECT SUMMARY
 Mutations in PTEN-induced kinase 1 (PINK1) are associated with autosomal recessive forms of Parkinson's
disease (PD). In the mitochondrion, full-length PINK1 is proteolytically processed to lower molecular weight
forms which are exported to the cytosol. While full-length PINK1 has been implicated in regulating mitophagy
and mitochondrial function, the understanding of the functional role(s) of endogenous cleaved PINK1 (c-
PINK1) in the brain is limited. Our recent research demonstrates a link of c-PINK1 and regulation of
mitochondrial trafficking and dendrite outgrowth via PKA. This model is supported by preliminary and
published data from our group, showing that loss of PINK1 function in vivo and in vitro impairs PKA-mediated
dendrite connectivity and mitochondrial trafficking, but the connections between these two mechanisms are
unresolved. The studies proposed will fill a critical void in our understanding of how c-PINK1 regulates PKA
signaling to enhance dendrite connectivity and mitochondrial trafficking in PD models. In Aim 1, the molecular
mechanisms by which PINK1 and dendrite-localized PKA protect dendrites from oxidative stress will be
elucidated using image-based and molecular biology approaches. Aim 2 will elucidate the mechanisms by
which PINK1 and PKA regulate mitochondrial trafficking in dendrites, and specifically test the hypothesis that
PINK1 acts through PKA to increase mitochondrial content by phosphorylating the mitochondrial trafficking
adaptor protein Miro2. Aim 3 will determine the mechanisms by which PINK1/PKA activation modulates
neurite outgrowth. This work is expected to have an impact on health and human diseases in three areas. First,
characterizing the PINK1-PKA signaling pathway will identify new protective mechanisms by which this novel
signaling axis maintains dendrite homeostasis. Second, experiments proposed in Aims 1 and 2 will help us
understand how PINK1 activates PKA signaling in mitochondria and dendrites regulate mitochondrial
trafficking and protect dendrites from oxidative stress. Third, since dysregulation of PKA signaling,
mitochondrial function, neurotrophic signaling, and loss of dendrites are implicated in multiple
neurodegenerative diseases, identifying new dendrite-protective mechanisms can lead to new targeted, rational
therapies via enhanced protective PKA signaling.

## Key facts

- **NIH application ID:** 9891110
- **Project number:** 5R01NS105783-03
- **Recipient organization:** UNIVERSITY OF NEVADA RENO
- **Principal Investigator:** RUBEN K DAGDA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $313,272
- **Award type:** 5
- **Project period:** 2018-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9891110

## Citation

> US National Institutes of Health, RePORTER application 9891110, Regulation of Dendrite Homeostasis by PINK1 and PKA in Models of Parkinson's Disease (5R01NS105783-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9891110. Licensed CC0.

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