Blocking a Protein’s Punch
Jeffery Molkentin’s discovery surrounding necrosis and the cyclophilin D protein was a classic example of a scientist looking for one thing but finding another. Molkentin was examining the role of the signaling protein calcineurin in heart muscle injury. Calcineurin acts on the cell nucleus but when Molkentin blocked its action with the drug cyclosporin, the mitochondria were protected instead. Whatever was saving the mitochondria from calcium flooding, it wasn’t calcineurin. Molkentin worked his way through a series of gene knockouts to identify the protein that was resisting mitochondrial damage—cyclophilin D.
Since Molkentin’s 2005 Nature paper reporting that blocking cyclophilin D rescued heart muscle cells’ mitochondria from necrotic swelling, the treatment possibilities have expanded beyond the heart. A few months later, the late Stanley Korsmeyer, then an HHMI investigator at Dana-Farber Cancer Institute, reported similar results after inactivating the cyclophilin D gene in a mouse model of cerebral stroke: neurons in the brain were protected after ischemia and did not die.
Since then, researchers using drugs or genetic knockouts have reported encouraging results in a variety of mouse models of degenerative diseases. Paolo Bernardi and colleagues at the University of Padua, Italy, used a cyclophilin D inhibitor on a form of muscular dystrophy that involves defects in collagen, successfully protecting the animals’ mitochondria from damage. By crossing Molkentin’s cyclophilin D-null transgenic mouse and a mouse model of Alzheimer’s disease, Shi Du Yan at the Columbia University College of Physicians and Surgeons showed that cyclophilin D deficiency improved the animals’ learning and memory. Mitochondria in the animals’ cells resisted swelling normally induced by the amyloid-beta protein accumulation that is a marker for Alzheimer’s.
Crossing Molkentin’s cyclophilin D mouse with mice carrying the superoxide dismutase gene involved in amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease) significantly delayed progression of the disease, according to Qing Chang and colleagues at the Johns Hopkins University School of Medicine. “This work defines a new mitochondrial mechanism for motor neuron degeneration in ALS,” says Chang.