# Neuron death in Parkinson's disease: The role of Trib3

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2022 · $391,387

## Abstract

The ultimate goal of the proposed research is to create innovative means to halt the progression of neuron
degeneration in Parkinson's disease (PD). Present treatments alleviate the symptoms of PD, but not its
advancement and there is therefore a major need for new ideas and approaches to slow or stop the relentless
degeneration of neurons that occurs in this disorder. The core idea here is that irrespective of the initiating
causes of PD, neuron degeneration and death are promoted by dysregulation of shared distal pro-death
pathways and that targeting these pathways and/or their components has the potential to stop or slow disease
progression. This renewal continues to focus on the protein Trib3. Our findings have shown that Trib3 is
induced by multiple cellular stresses associated with PD and is elevated in dopaminergic substantia nigral
neurons of PD patients as well as in multiple cellular models of PD. Trib3 is both sufficient and necessary to
promote neuron degeneration and death in cellular models of PD and its deletion or suppression in such
models provides protection from neurite degeneration and death. Examination of the upstream regulatory
pathway of Trib3 induction in PD models reveals necessary involvement of the transcription factors ATF4 and
CHOP/DDIT3 and preliminary data show that interference with this pathway by the drug “adaptaquin” blocks
Trib3 induction and neuron death and degeneration in cellular PD models. Regarding mechanism, our studies
show that Trib3 interacts with Parkin (a neuroprotective protein whose loss or dysfunction leads to an early
onset form of PD in humans and to neuron degeneration in cell and animal models) in living cells and that this
association leads to Parkin depletion via the COP1 E3 ligase. These findings lead to the hypothesis that the
chronic cellular stresses that initiate the path towards neuron degeneration and death in PD elevate Trib3
expression and that this contributes to the slow and inexorable progression of the disease at least in part by
diminishing levels of Parkin. To exploit these observations so as to move forward towards targeting Trib3 for
the purpose of alleviating the progression of PD in patients, 3 specific aims are proposed. These are: 1) To test
the hypothesis that conditional deletion of Trib3 in substantia nigral dopaminergic neurons of living mice will
provide protection in models of Parkinson's disease. PD models will include treatment with 6-OHDA and a-
synuclein over-expression/exposure to a-synuclein fibrils. 2) To test the hypothesis that Trib3 contributes to
neuron death in PD by interacting with and depleting neuronal levels of the protective protein Parkin and to
define the bases for this interaction so as to provide strategies to disrupt this association for potential
therapeutic purposes. 3) To test the hypothesis that interference with Trib3 induction by the drug “adaptaquin”
will protect neurons in cellular and animal models of PD. The successful outcome of ...

## Key facts

- **NIH application ID:** 10308672
- **Project number:** 5R01NS072050-10
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** LLOYD A GREENE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $391,387
- **Award type:** 5
- **Project period:** 2012-06-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10308672

## Citation

> US National Institutes of Health, RePORTER application 10308672, Neuron death in Parkinson's disease: The role of Trib3 (5R01NS072050-10). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10308672. Licensed CC0.

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