Michael Rapé, PhD: Targeting Mitochondria to Treat Parkinson’s Disease

In his lab at The University of California, Berkeley, Dr. Rapé and his team study cellular stress response pathways and how they orchestrate development and protect against disease. When something goes awry in a cell, stress responses remove broken or defective machinery.

“Stress responses basically clean up under difficult conditions, like FEMA after a natural disaster, to get rid of misfolded, defective, broken parts of the cell,” said Dr. Rapé. “Our research often starts by doing unbiased genetic screens, where we try to discover new stress responses.”

One day while running a genetic screen on cells that were exposed to stressors, Dr. Rapé and his team made a discovery that would open a new research path. “We found a very interesting gene that had a very strange behavior,” said Dr. Rapé.

After running further experiments, the team found that the gene encodes an enzyme that plays an important role in the reductive stress response. “The reductive stress response is a regulatory mechanism that controls the activity of a very important series of complexes in mitochondria that is really essential for energy generation by neurons,” said Dr. Rapé.

According to Dr. Rapé, when this stress response fails, it can lead to mitochondrial dysfunction and cell death, contributing to disease. “It's essential in every cell, but particularly important in neurons,” he said. “And so, after we discovered these stress responses, we tried to understand them from a cellular as well as from a biochemical perspective.”

After teasing apart the core components of the reductive stress response, Dr. Rapé and his team developed a small molecule designed to exploit this protective pathway and restore mitochondrial function.1 Even at this stage, however, Parkinson’s disease was not on the team’s radar.

Instead, they turned to a rare mitochondrial disorder known as COX deficiency, caused by genetic mutations that impair cellular energy production. “Using neurons engineered to model the disorder, the researchers tested their compound and found that it improved energy production in the cells,” said Dr.Rapé “The findings suggested that activating this pathway could help cells recover from mitochondrial dysfunction.”

That insight prompted a broader question. Mitochondrial impairment is a hallmark of several neurodegenerative diseases, including Parkinson’s.2 Could the same approach protect vulnerable neurons?

“If you have a neuron you want to keep alive, you might want to make those stress responses more powerful, more active,” said Dr. Rapé . “And we now found ways we can do this with small molecules. This was really exciting. At this point I went to SPARK NS.”Dr. Rapé applied to the SPARK NS Translational Research Program, 2025 Cohort, with a proposal to develop a novel therapeutic for Parkinson’s disease.

With his project, “Restoring Mitochondrial Function in Parkinson’s Disease,” Dr. Rapé is working to translate his findings into a therapeutic strategy for the disease.

Through the program, the research team have worked closely with medicinal chemistry experts to optimize their lead compound. “The advisors at SPARK NS are really absolutely wonderful—the time that they spent, the insight that they provided,” he said. “We improved the molecule by about 1,000-fold from what we had before.”

Dr. Rapé is no stranger to drug development. In addition to his academic work, he serves as the founding head of the Division of Molecular Therapeutics at UC Berkeley and has co-founded four biotechnology companies. One of these, Nurix Therapeutics, develops small molecules for targeted protein degradation, with a lead candidate currently in Phase 3 clinical trials for B cell lymphoma.

“We’ve seen how tuning this stress signaling can be very helpful for patients,” Dr. Rapé said. “For our cancer patients, it’s amazing what we’ve seen.”

Now, he hopes to bring that same promise to Parkinson’s disease. Early findings suggest that their small molecule may offer a novel path forward.

“I think it shows that basic science is very important for drug discovery,” said Dr. Rapé. “It’s a nice example of how we can come up with something new, a completely new idea to help treat Parkinson’s.”