By Megan Mayerle, PhD

July 2, 2019

Huntington’s disease (HD) is a deadly neurodegenerative disorder. While the central nervous system is the body system most affected by HD, many patients also experience non-neuronal issues. HD patients suffer also from skeletal muscle atrophy, cardiovascular diseases, and heart failure, none of which are targeted by the currently available HD drugs.

The heart and other muscles require a lot of energy to function properly and rely on mitochondria as a source for this energy. Mitochondria are dynamic, forming long tubules that then fragment only to fuse into tubules once again. This process is in part controlled by the protein Drp1. Under stresses like Huntington’s disease Drp1 binds to Fis1, another mitochondrial protein, and becomes hyperactivated. Hyperactive Drp1 disrupts mitochondrial function, causing excessive mitochondrial fragmentation, ROS production and oxidative stress, and a loss of membrane potential.

The cardiac cells of HD patients often contain dysfunctional mitochondria. In a paper recently published in the Journal of Molecular and Cellular Cardiology, Stanford researchers Drs. Amit Joshi and Daria Mochly-Rosen and colleagues set out to determine whether or not hyperactive Drp1 underlies this mitochondrial dysfunction.

The researchers differentiated induced pluripotent stem cells (iPSCs) containing a disease-linked version of the Huntington protein to cardiomyocytes (iPSC-CMs). They found that the disease-associated Huntington protein did cause reduced energy production and fragmentation in iPSC-CMs, and that such damaged mitochondria accumulate in cellular lysosomes, where they cause lysosomal dysfunction. Joshi and colleagues were further able to show that P110, a synthetic peptide that selectively inhibits Drp1’s interaction with Fis1, when introduced into the iPSC-CMs, could block these negative effects.

The researchers also showed that P110 has similar mitochondrial benefits in a mouse model of Huntington’s disease, though the researchers have yet to fully characterize how P110 treatment affects cardiac function and lifespan of these HD mice. Joshi and colleagues hope that their studies with P110 will help pave the way for the development of a therapeutic that improves cardiac and muscular function for HD patients.

A.U. Joshi, A.E. Ebert, B. Haileselassie, and D. Mochly-Rosen all contributed to this study.  This work was supported, in part, by Takeda Pharmaceuticals' Science Frontier Fund and HL52141, a grant to DMR. Although Takeda sponsored, in part, the cost of the project, experiments were designed and executed entirely at Stanford University and Takeda has no ownership on the findings.