Cholesterol-lowering drug aids mitochondria in Parkinson’s models
Probucol, no longer in wide use, may open new way of treating disease
Probucol, a cholesterol-lowering medication previously used in Western countries, improved motor function and lengthened the lifespan of treated animals in models of Parkinson’s disease, a study found.
Identified as a potential Parkinson’s treatment through an artificial intelligence (AI)-based search, probucol was found to promote mitophagy, the cellular pathway that recycles mitochondria, a cell’s powerhouses.
Targeting the same molecular pathways affected by probucol might be a valuable way of treating Parkinson’s, which is often marked by mitochondrial dysfunction, the researchers noted.
“We used the AI-platform IBM Watson to efficiently identify currently approved drugs that could potentially be re-purposed as therapies for Parkinson’s disease,” Angus McQuibban, the study’s senior author and a biochemistry professor at the University of Toronto, said in a press release.
Mitochondria, affected by Parkinson’s, work to provide cells with energy
The study, “An AI-guided screen identifies probucol as an enhancer of mitophagy through modulation of lipid droplets,” was published in PLOS Biology.
Mitochondria play a critical role in energy production within cells, also serving as a manufacturing site of cellular components. Problems with mitochondria are seen in Parkinson’s and many other neurological disorders, and they are thought to contribute to the dysfunction and death of nerve cells, which normally require a lot of energy to function.
When mitochondria become damaged, they are usually recycled through a process called mitophagy. These organelles are broken down into simple molecules that can be repurposed by the cell to make new mitochondria or other structures.
Evidence indicates that this process is impaired in Parkinson’s disease, with many Parkinson’s-linked genes being known to play direct or indirect roles in mitophagy, including the genes SNCA and LRRK2, both strongly associated with the disease.
Previous research identified molecules that can promote mitophagy, but to date these compounds are lethal to cells, too toxic to be used as medicine.
McQuibban and colleagues at his university and Toronto Western Hospital set out to identify existing treatments that activate mitophagy and could potentially be repurposed for Parkinson’s.
To do so, they used the IBM Watson for Drug Discovery, “an AI program run on a supercomputer that analyzes the published literature for patterns of key words, phrases, and juxtapositions,” the release stated.
Basically, the scientists fed the computer data from papers describing known mitophagy activators, allowing the AI to identify a “semantic fingerprint” for how these molecules are usually described. Then the AI combed through scientific literature, looking for other molecules described using many of the same terms.
This screening identified 79 candidates, which the researchers tested in lab-grown cells exposed to a mitochondrial poison as a preliminary assessment of mitophagy activation. The three most promising candidates were selected for further testing in other mitophagy assays, and results identified probucol as a promising mitophagy activator.
Probucol, sold under brand names including Lorelco, has been prescribed to lower cholesterol levels. While still in use across Japan and China, the therapy was withdrawn from the U.S. and European markets due to certain safety issues, including a reduction in the levels of high-density lipoprotein, or “good,” cholesterol.
The medication is known to block the activity of ABCA1, a protein that helps to regulate the movement of lipid droplets. Lipid droplets are fat-rich cellular organelles that help to maintain mitochondrial integrity during stress, and which have been suggested to accumulate in neurons in Parkinson’s models.
Probucol may help to clear damaged mitochondria from cells
Researchers tested probucol in fruit fly and zebrafish models of Parkinson’s induced by exposure to a neurotoxic chemical. In both animal models, probucol’s use led to improvements in survival and motor function — flies were able to climb higher and fish could swim farther.
Probucol treatment also reduced the severity of disease manifestations in flies with a genetic mutation that causes mitochondrial problems.
“Across toxin-based and genetic models of mitochondrial damage and [Parkinson’s] in two different species, probucol improved survival, locomotor function, and reduced the loss of [dopamine-producing] neurons,” the researchers wrote. Of note, Parkinson’s is caused by the death of neurons that produce the chemical messenger dopamine.
Further testing in fruit flies and lab-grown human cells showed that probucol’s effects were dependent on the ABCA1 protein, its known target, and on lipid droplets. Probucol was no longer able to activate mitophagy when either ABCA1 or lipid droplet expansion was suppressed.
Lipid droplets tended to get bigger when cells had mitochondrial damage, but this effect was diminished by probucol treatment, the researchers also noted.
These findings suggest that ABCA1 “likely acts as a mediator of crosstalk between LD [lipid droplet] dynamics and mitophagy since LDs are required for the mitophagy enhancement conferred by probucol,” the team wrote.
“Our study showcased a dual in silico [in computers]/cell-based screening methodology that identified known and new mechanisms leading to mitophagy enhancement,” McQuibban said.
“Given the linkage between lipid droplet accumulation and ABCA1, it seems likely that probucol enhances mitophagy through mobilization of lipid droplets. Targeting this mechanism may be advantageous” in treating Parkinson’s, McQuibban added.
Exploring whether other cholesterol-lowering medications have similar mitophagy-activating effects “may represent an interesting avenue for future inquiry,” the researchers added.
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