BPAN Researcher Finds Compounds that Restore Mitochondrial Health
by Patricia Wood
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Dr. Arcangela Iuso, of Helmholtz Zentrum Munich, in Munich, Germany. Her BPAN research grant funded by NBIADA was titled, “Understanding the functional link between mutations in WDR45 and reduced respiratory chain complex I (RCCI) activity, and exploring cAMP modulation as a therapeutic approach.” |
Most research on BPAN has focused on problems with autophagy, a process that helps cells clear out waste. But in a recently completed study supported by the NBIA Disorders Association, a team led by Dr. Arcangela Iuso at Helmholtz Zentrum Munich in Germany, took a new approach. They asked whether mutations in the WDR45 gene which lead to damaged mitochondria (the energy powerhouses of cells) might also play a role in how BPAN develops.
The team first spotted this mitochondrial defect in the brain tissue of a BPAN mouse model. It appeared to be linked to the malfunctioning of a key mitochondrial enzyme known as Respiratory chain Complex I (RCCI), a discovery that Iuso co-authored in a 2021 publication available here.
For this new research, Iuso’s team studied skin and brain cells from BPAN patients. The brain cells were made in the lab by first turning skin cells into stem cells, then guiding them to develop into two types of brain cells: support cells called astrocytes and nerve cells called neurons.
They found signs of mitochondrial problems in both skin cells and astrocytes — but not in neurons. This suggests neurons may have ways to protect themselves from the damage.
To test whether the mitochondrial issues could be fixed, three different compounds were applied to skin cells to see if they could potentially restore the mitochondrial enzyme activity of RCCI in a laboratory setting.
These compounds were forskolin, resveratrol and b2cAMP. Forskolin and resveratrol are natural compounds sold as supplements, while b2cAMP is a natural compound found in all cells as part of the body’s signaling mechanisms. It is not sold as a supplement or medication.
All three compounds helped, but b2cAMP and forskolin were especially effective, fully restoring mitochondrial function.
To advance this research, the team will conduct long-term studies on astrocytes to evaluate whether the positive effects of these compounds are sustained. Additionally, the focus will expand to explore other cellular defects associated with WDR45 mutations, such as autophagy dysfunction and ER stress, with the goal of understanding how these compounds may correct multiple aspects of BPAN pathophysiology.
The next phase will involve testing these compounds in the available BPAN mouse model to evaluate their therapeutic potential in vivo. This critical step will provide valuable insights for translating these findings into clinical applications.
The research team is currently seeking additional funding from government grants and philanthropic organizations to move this work forward which will open the door to potential new treatments focused on improving mitochondrial health.