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Parkinson’s Disease: Anti-cholesterol Drug Found To Improve Motor Function, Survival And Neuron Loss

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A new study finds an approved drug that has the potential to be repurposed as therapy for Parkinson’s disease.

A new study published on March 2nd in the open-access journal PLOS Biology by Angus McQuibban and colleagues from the University of Toronto, Canada, suggests that an anti-cholesterol drug can enhance the disposal of damaged mitochondria, the energy-producing components of cells affected by Parkinson’s disease.

The exact pathogenic pathway that leads to Parkinson’s disease (PD) is not fully understood; however, mitochondrial dysfunction and the failure to dispose of faulty mitochondria, a process known as mitophagy, are known to contribute to the disease.

The team looked for compounds that may improve the mitophagy process since they knew at least five genes involved in PD were associated with poor mitophagy in some way.

Consequently, they searched for compounds that could enhance the mitophagy process. Although several compounds were discovered, most of them were detrimental to cells, rendering them unsuitable as potential drug candidates.

This made the authors wonder if the papers that talk about the known enhancers could lead them to other papers that talk about compounds that haven’t been linked to improving mitophagy before but use some of the same words.

Finding patterns of such “semantic similarity” is one of the main talents of IBM Watson for Drug Discovery, an AI software run on a supercomputer that examines the published literature for patterns of important words, phrases, and juxtapositions.

Using the algorithm, the scientists created a semantic “fingerprint” of genuine mitophagy enhancers. They then searched for comparable fingerprints in the literature on a collection of more than three thousand candidates from a pharmacological database.

A mitochondrial poison was used to test the top 79 candidates in cell culture.

After tests on many different mitophagy assays, the three top candidates from that assay were evaluated, and probucol, a medication used to decrease cholesterol, was shown to have the greatest efficiency and probable safety profile.

In two separate animal models of Parkinson’s disease, probucol was also found to enhance motor function, survival, and neuron loss (PD is primarily a movement disorder).

For Probucol to have an effect on mitophagy, lipid droplets had to form and do their job. Lipid droplets are temporary cell structures that help keep mitochondrial integrity during times of stress and that build up in Parkinson’s disease.

Since probucol is able to stimulate mitophagy only when levels of ABCA1, a protein involved in lipid transport, are high, it seems plausible that ABCA1 mediates the involvement of lipid droplets in mitophagy.

McQuibban stated that their study demonstrated a screening technique, involving both in silico and cell-based approaches, that identified new and previously known mechanisms for enhancing mitophagy. It is probable that probucol facilitates mitophagy by mobilizing lipid droplets, given the connection between lipid droplet accumulation and ABCA1. According to McQuibban, targeting this pathway may prove beneficial.

Source: 10.1371/journal.pbio.3001977

Image Credit: Getty

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