In the United States, more than 30,000 people suffer from the incurable neurodegenerative genetic disorder Huntington’s disease (HD). Now, researchers have identified two regulatory proteins vital to eliminating the misfolded proteins that cause the disease.

HD is an inherited disease in which parts of the brain degenerate. The disease affects muscle coordination and leads to cognitive decline and psychiatric problems.

The study, conducted by researchers at the University of California, San Diego School of Medicine, is published in the online issue of Science Translational Medicine.

According to lead researcher, Albert R. La Spada, M.D., Ph.D., professor of cellular and molecular medicine, chief of the Division of Genetics in the Department of Pediatrics and associate director of the Institute for Genomic Medicine at the UC San Diego: “The findings explain a fundamental aspect of how HD wreaks havoc within cells and provides clear, therapeutic opportunities.”

He continued: “We think the implications are significant. It;s a lead we can vigorously pursue, not just for Huntington’s disease, but also for similar neurodegenerative conditions like Parkinson’s disease and maybe even Alzheimer’s disease.”

In the study, the team focused on PGC-1alpha, a protein which helps regulate the production and operation of mitochondria. Mitochondria are tiny organelles in cells that produce power. This power is vital for cells to function.

La Spada said:

“It’s all about energy. Neurons have a constant, high demand for it. They’re always on the edge for maintaining adequate levels of energy production. PGC-1alpha regulates the function of transcription factors that promote the creation of mitochondria and allow them to run at full capacity.”

In a mouse model of HD, the researchers found that elevated levels of PGC-1alpha virtually eliminated the misfolded proteins that cause HD.

PGC-1alpha in particular impacted expression of another protein that is crucial for autophagy. However, for neurons that need to last a lifetime, self-renewal is crucial for survival. Autophagy is a process whereby healthy cells degrade, recycling old, unneeded or dangerous particles and products, such as oxidative, damaging molecules generated by metabolism.

La Spada, explained:

“Mitochondria get beat up and need to be recycled. PGC-1alpha drives this pathway through another protein called transcription factor EB or TFEV. We were unaware of this connection before, because TFEB is a relatively new player, though clearly emerging as a leading actor. We discovered that even without PGC-1alpha induction, TFEB can prevent htt aggregation and neurotoxicity.”

The researchers crossbred mice with HD with mice that generated elevated levels of PGC-1alpha and found that they showed significant improvement. According to the researchers, the generation of misfolded proteins was essentially eliminated and the mice behaved normally.

La Spada, said: “Degeneration of brain cells is prevented. Neurons don’t die.” He continued saying that both PGC-1alpha and TFEB provide two new therapeutic targets for HD.

He concluded: “If you can induce the bioenergetics and protein quality control pathways of nervous system cells to function properly, by activating the PGC-1alpha pathway and promoting greater TFEB function, you stand a good chance of maintaining neural function for an extended period of time. If we could achieve the level of increased function necessary to eliminate misfolded proteins, we might nip the disease process in the bud. That would go a long way toward treating this devastating condition.”

Written by Grace Rattue