Abstract Details

Title In silico drug screening by using genome-wide association study (GWAS)-data repurposed dabrafenib, an anti-melanoma drug, for Parkinson’s disease

Topic Movement Disorders

Presentation(s) P3 - Poster Session 3 (5:30 PM-6:30 PM)

Poster/Presentation
Number 10-031

Objective Parkinson’s disease (PD) is a neurodegenerative disorder characterized by dopaminergic neuron loss. At present, there are no drugs that stop the progression of PD. In this study, our objective is to identify the disease-modifying drug for PD.

Background The discovery of new drugs is an expensive and time-consuming process. Therfore, drug repurposing, which is the identification of new indications for existing drugs, is thought to be a promising strategy for intractable diseases such as PD. As with other multifactorial genetic disorders, genome-wide association studies (GWASs) found multiple risk loci for PD, although their clinical significance remains uncertain.

Design/Methods Here, we report the identification of candidate drugs for PD by a method using GWAS data and in silico databases. Then, we examined whether those candidates exert the neuroprotective effects in in vitro and in vivo PD model.

Results

We identified 57 Food and Drug Administration (FDA)-approved drug families as candidate neuroprotective drugs for PD. Among them, dabrafenib, which is a B-Raf kinase inhibitor and is approved for malignant melanoma, showed remarkable cytoprotective effects in neurotoxin-treated SH-SY5Y cells and mice. Dabrafenib inhibited apoptosis, enhanced the phosphorylation of extracellular signal-regulated kinase (ERK), and inhibited the phosphorylation of c-Jun NH₂-terminal kinase. Dabrafenib targets B-Raf, and we confirmed a protein-protein interaction between B-Raf and Rit2, which is coded by RIT2, a PD risk gene in Asians and Caucasians. A reduced expression of RIT2 was reported in the substantia nigra of patients with PD. In RIT2-knockout cells, the phosphorylation of ERK was reduced, and dabrafenib treatment improved the ERK phosphorylation. These data indicated that dabrafenib exerts protective effects against neurotoxicity associated with PD.

Conclusions

We identified dabrafenib as a candidate of disease-modifiying drug for PD. Furthermore, our results suggest that this in silico drug screening system is useful in other neurodegenerative diseases, such as Alzheimer’s disease and amyotrophic lateral sclerosis.

Authors/Disclosures
Takeshi Uenaka, MD PRESENTER	No disclosure on file
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Hideki Mochizuki, MD (Juntendo University)	No disclosure on file
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