Two proteins offer a 'clearer' way to treat Huntington's disease

July 11, 2012, University of California - San Diego
This is a human neuron. UC San Diego scientists have identified a pair of proteins that help clear away other misfolded proteins responsible for the progressive degeneration of brain cells in Huntington's disease. Credit: UC San Diego School of Medicine

In a paper published in the July 11 online issue of Science Translational Medicine, researchers at the University of California, San Diego School of Medicine have identified two key regulatory proteins critical to clearing away misfolded proteins that accumulate and cause the progressive, deadly neurodegeneration of Huntington's disease (HD).

The findings explain a fundamental aspect of how HD wreaks havoc within cells and provides "clear, therapeutic opportunities," said principal investigator Albert R. La Spada, MD, PhD, professor of cellular and , chief of the Division of Genetics in the Department of Pediatrics and associate director of the Institute for Genomic Medicine at UC San Diego.

"We think the implications are significant," said La Spada. "It's a lead we can vigorously pursue, not just for Huntington's disease, but also for similar like Parkinson's disease and maybe even Alzheimer's disease."

In HD, an inherited mutation in the huntingtin (htt) gene results in misfolded htt proteins accumulating in certain central , leading to of involuntary movement control, and psychological problems. More than 30,000 Americans have HD. There are no effective treatments currently to either cure the disease or slow its progression.

La Spada and colleagues focused on a protein called PGC-1alpha, which helps regulate the creation and operation of mitochondria, the tiny organelles that generate the fuel required for every cell to function.

"It's all about energy," La Spada said. "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 that promote the creation of mitochondria and allow them to run at full capacity."

Previous studies by La Spada and others discovered that the mutant form of the htt gene interfered with normal levels and functioning of PGC-1alpha. "This study confirms that," La Spada said. More surprising was the discovery that elevated levels of PGC-1alpha in a mouse model of HD virtually eliminated the problematic misfolded proteins.

Specifically, PGC-1alpha influenced expression of another protein vital to autophagy – the process in which healthy cells degrade and recycle old, unneeded or dangerous parts and products, including oxidative, damaging molecules generated by metabolism. For neurons, which must last a lifetime, the self-renewal is essential to survival.

"Mitochondria get beat up and need to be recycled," La Spada said. "PGC-1alpha drives this pathway through another protein called transcription factor EB or TFEB. 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."

In their experiments, HD mice crossbred with mice that produced greater levels of PGC-1alpha showed dramatic improvement. Production of misfolded proteins was essentially eliminated and the mice behaved normally. "Degeneration of brain cells is prevented. Neurons don't die," said La Spada.

PGC-1alpha and TFEB provide two new therapeutic targets for , according to La Spada. "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."

Explore further: Neurological disorder impacts brain cells differently

Related Stories

Neurological disorder impacts brain cells differently

November 9, 2011
In a paper published in the Nov. 9 issue of the Journal of Neuroscience, researchers at the University of California, San Diego School of Medicine and University of Washington describe in deeper detail the pathology of a ...

Recommended for you

Researchers investigate changes in white matter in mice exposed to low-frequency brain stimulation

June 19, 2018
A team of researchers at the University of Oregon has learned more about the mechanism involved in mouse brain white matter changes as it responds to stimulation. In their paper published in Proceedings of the National Academy ...

Left, right and center: mapping emotion in the brain

June 19, 2018
According to a radical new model of emotion in the brain, a current treatment for the most common mental health problems could be ineffective or even detrimental to about 50 percent of the population.

Cell type and environment influence protein turnover in the brain

June 19, 2018
Scientists have revealed that protein molecules in the brain are broken down and replaced at different rates, depending on where in the brain they are.

Often overlooked glial cell is key to learning and memory

June 18, 2018
Glial cells surround neurons and provide support—not unlike hospital staff and nurses supporting doctors to keep operations running smoothly. These often-overlooked cells, which include oligodendrocytes and astrocytes, ...

Electrically stimulating the brain may restore movement after stroke

June 18, 2018
UC San Francisco scientists have improved mobility in rats that had experienced debilitating strokes by using electrical stimulation to restore a distinctive pattern of brain cell activity associated with efficient movement. ...

Neuroscientists map brain's response to cold touch

June 18, 2018
Carnegie Mellon University neuroscientists have mapped the feeling of cool touch to the brain's insula in a mouse model. The findings, published in the June 15 issue of Journal of Comparative Neurology, provide an experimental ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.