Dr. Al La Spada’s work in the realm of Huntington’s disease first drew national attention in 2006, with a coveted cover story in Cell Metabolism. At the time, La Spada and his colleagues published findings related to the molecular pathogenesis of Huntington’s disease (HD). Huntington’s affects an estimated 30,000 people in the United States, and it is characterized by loss of motor control and cognitive functions, as well as depression or other psychiatric problems.
La Spada, UW associate professor in laboratory medicine, medicine and neurology, and his team continue to study the debilitating condition and other neurodegenerative diseases. He presented his latest findings in late 2008 in a plenary session at the annual meeting of the American Society of Human Genetics in Philadelphia.
“The work that we presented was a follow up to those studies,” said La Spada. More specifically, La Spada and colleagues studied cases in which a protein (known as PGC-1 alpha) was not functioning normally in those affected by HD. They wanted to learn whether or not researchers could reduce HD symptoms by increasing the function of the protein. Researchers found the mice showed improved neurological function.
An unexpected finding was that the increased protein (PGC-1 alpha) eliminates protein that is already built up in the brain.
“All the major neurodegenerative diseases involve proteins that mis-fold and can’t be degraded, and then they build up in the brain and you can see them,” said La Spada. “That’s a pathological marker of HD.”
The findings have significant therapeutic implications because one class of drug that could potentially be used to treat HD symptoms is currently being tested in clinical trials in patients, said La Spada. His research team also found that drugs already on the market for cancer treatment could potentially treat HD by increasing a retinoic acid signaling pathway through a receptor known as PPAR delta. PPAR delta controls many physiological functions, especially in the realm of development and metabolism.
“Our work shows that this is a potential pathway to be studied further as a treatment for HD, with the very exciting aspect being that if we’re right, then there are compounds on the shelf we could either take as lead compounds to further develop or just immediately try them in HD patients,” said La Spada. One of the next steps for La Spada and his colleagues is to try to get a better understanding how the protein (PGC-1 alpha) leads to the elimination of the aggregates.
“We also need to understand, and need to demonstrate that the [receptor] PPAR delta effect, which we’ve now shown in nerve cells, will be applicable in the HD mice,” La Spada added.
Any sort of development in HD that could have ramifications for therapy development in the foreseeable future is exciting, said La Spada. While he and his colleagues submit their findings for publication in a scientific journal, they did not wait to share the research with the public.
“It made sense to present the findings,” said La Spada. “I’m of the philosophy that scientific advances that might benefit patients suffering from devastating diseases for which there is no treatment shouldn’t be suppressed — because time is passing. Many people are waiting for a new treatment that may give them some hope. So that’s the way I viewed it.”