Induction Of Pgc-1 Alpha Expression In Huntington's Disease Transgenic Mice Rescues Neuronal Dysfunction And Neurodegeneration

Studies of HD and other related neurodegenerative disorders, such as Parkinson's disease, have highlighted the importance of mitochondrial function and energy production in the maintenance of normal neural function. However, there is currently no known cure for this fatal disease.

Albert La Spada, M.D., Ph.D., FACMG, Associate Professor and Director of the Center for Neurogenetics and Neurotherapeutics at University of Washington, Seattle, and his research team have been instrumental in establishing a new paradigm for HD neurodegeneration by linking nuclear transcription interference with mitochondrial dysfunction at the level of the transcription co-activator PGC-1a – an important factor that regulates mitochondria.

In their latest work, Dr. LaSpada and his research group sought to determine if PGC-1a can ameliorate any clinical symptoms of HD by performing genetic studies in a mouse model of HD. Their findings indicate that increased PGC-1a action does improve neurological defects in HD mice and results in reduced amounts of protein aggregates – a key pathological feature of most neurodegenerative disorders.

Specifically, the current results indicate that PPARd (a peroxisome proliferator-activated receptor that is positively modulated by PGC1-a) interacts with the huntingtin protein, and altered function of PPARd contributes to HD neurodegeneration. If PPARd is involved in this neurological disease, then tractable therapies to boost PPARd would be immediately available, as two recent lines of investigation make PPARd an attractive therapeutic target: (1) highly selective and powerful pharmacological agonists for PPARd have been developed and are currently being studied in clinical trials in humans; and 2) PPARd mediates pro-survival signaling in response to retinoic acid, a compound that has been used for years to treat human patients with leukemia and brain tumors.

"My colleagues and I are very excited about the surprising results of our most recent research on Huntington's disease, since the findings could ultimately lead to the first potential treatment for this currently fatal disease," LaSpada said. "Furthermore, our findings suggest there are drugs that are already available and currently being used in human patients that could be possible new therapies for Huntington's disease."

Albert R. La Spada, M.D., Ph.D., FACMG, is Director of the Center for Neurogenetics and Neurotherapeutics and Associate Professor of Laboratory Medicine, Medicine (Medical Genetics), Pathology, and Neurology at the University of Washington, Seattle. La Spada's research efforts have uncovered a number of connections between pathways involved in transcription and neuron dysfunction. His current work focuses on investigating the molecular basis of neurodegenerative disease.

This research was presented at the 58th Annual Meeting of The American Society of Human Genetics (ASHG) in Philadelphia, Pennsylvania on November 11-15, 2008.