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 these studies will promote development of a Trib3-targeted therapy that alters the course of degenerative progression in PD.

Public Health Relevance

The studies proposed in this project seek to understand how elevated levels of the protein Trib3 contribute to the degeneration and death of dopaminergic neurons that occurs in Parkinson's disease and to assess means to block either Trib3 elevation or its destructive actions in this disorder. Success of these studies has a realistic potential for development of drugs that inhibit the progressive degeneration and loss of neurons in Parkinson's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS072050-09
Application #
10067574
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Cheever, Thomas
Project Start
2012-06-01
Project End
2022-12-31
Budget Start
2021-01-01
Budget End
2021-12-31
Support Year
9
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Pathology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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