Albert LaSpada of the University of Washington in Seattle was able to reverse Huntington symptoms in a mouse model of the disease using a transgene expressing PGC1alpha. He presented details of his study on Wednesday, but gave a little additional background at a press conference this afternoon. It’s one of those lovely genetics discovery stories that not only offers promise for a devastating disease, but comes together so neatly when looked at in hindsight, I just had to relate it.
LaSpada was a grad student with Kenneth Fischbeck at the University of Pennsylvania in the late 1980s and early 1990s. Together, in 1991, they discovered the genetic underpinnings of X-linked spinal and bulbar muscular atrophy. It was caused by a gene with an abberant trinucleotide repeat. Two years later it was found that Huntington’s disease (HD) worked in much the same way, with an repeated CAG sequence in the huntingtin protein creating a long string of the amino acid glutamine. These repeats prevent huntingtin from folding properly and make it clump up in the brain — a hallmark of many neurological diseases. The relatively high profile of HD made for a lot of excitement LaSpada says, and now there are at least nine of these so-called polyglutamine diseases known.
After he became a PI himslef, LaSpada had a trainee looking to treat HD who was going to test a cannabinoid drug in a mouse model for the disease. LaSpada predicted that the drug might interfere with temperature regulation, so he suggested that they observe temperature closely. They found surprisingly that untreated mice had very low body temperatures, leading them to speculate about the metabolic pathways that might have been contributing to this. In HD there’s the hallmark unfolded proteins, but there’s also dysregulation of transcription and mitochondrial dysfunction. But nothing linked the pathways together. Using the mouse model they were able to show how huntingtin aggregates interfered with the activity of PGC1alpha, a transcriptional co-activator involved in mitochondrial function in the brown fat by which mice maintain their body temperature. They engineered an HD model mouse to overexpress PGC1alpha and it both improved neurological function and cleared the huntingtin clumps. Screening for proteins that PGC1alpha interacts with reveals that it modulates the activity of PPARdelta. Another recent study LaSpada says, further shows that PPARdelta is involved in the response to retinoic acid, thus revealing two potential targets for drugs: ATRA, a chemotherapeutic that works like retinoic acid is already in use for promyelocytic leukemia, and GW 501516, a PPARdelta agonist has been used in clinical trials to modulate cholesterol and go after fat.
It seemed such a tidy path of discovery, definitely inspiring. Even the person following LaSpada at the press conference was a bit stunned. Before presenting his own results following humans with Gaucher disease, Hans Andersson at Tulane Univeristy in New Orleans just had to pause to say, “Cool. That’s a cool story!”