Unexpected Damaging Effects Found in Parkinson's Disease Drug Candidates

Parkinson's disease, the second most prevalent neurodegenerative disorder affecting over 10 million people globally, is primarily characterized by the inability of affected neural cells to effectively clear out dysfunctional mitochondria. Mitochondria, vital energy-producing structures within cells, also tend to leak toxins as they age, necessitating a process known as mitophagy—cellular quality control that removes damaged mitochondria to maintain health.

Recent research from the California Institute of Technology reveals concerning findings about potential treatments aimed at activating mitophagy pathways to combat Parkinson's. A study published in Science Advances titled "Putative PINK1/Parkin Activators Lower the Threshold for Mitophagy by Sensitizing Cells to Mitochondrial Stress" demonstrates that two drug candidates developed to stimulate mitophagy do not work as intended. Instead of facilitating healthy mitochondrial clearance, these drugs cause cellular damage, impairing mitochondrial health.

The research was led by William Rosencrans (Ph.D. '25), in collaboration with Professors Tsui-Fen Chou and David Chan. These drugs target two key genes, PINK1 and PARKIN, which are crucial for initiating mitophagy. The goal was to develop medicines that activate these genetic pathways to treat Parkinson's. However, the study found that rather than engaging these pathways properly, the drugs damage mitochondria, resembling a destructive approach rather than a corrective one.

Rosencrans explained the issue with an analogy: "Imagine your microwave is broken. Instead of fixing it, you smash it further with a sledgehammer—that might force you to throw it away, but it’s not a proper solution." Similarly, the drugs analyzed caused mitochondrial damage, misleading traditional testing assays which are not nuanced enough to differentiate between genuine pathway activation and damage.

These findings have broader implications, as many neurodegenerative diseases face issues related to mitochondrial quality control. The team is now working on developing new drugs that activate mitophagy without harming mitochondria. Rosencrans emphasizes the importance of basic research and understanding the mechanisms of drug action, especially given the large amounts of funding invested into drug development.

This study underscores the need for rigorous testing methods capable of accurately assessing how drugs interact with cellular pathways, and it highlights the potential pitfalls of current assays that may misidentify mitochondrial toxins as beneficial agents. Ultimately, improving our understanding of mitophagy and mitochondrial health could lead to more effective treatments for Parkinson's and related disorders.