In neurodegenerative diseases, such as Alzheimer and Parkinson, misfolded proteins form toxic traffic jams that stop neurons from functioning normally. As the neurons malfunction and eventually die, people experience symptoms ranging from memory loss to lack of motor coordination.

The good news is that these diseases may be reversible—if scientists can make the gnarls of mutant proteins disappear. But identifying drugs that can disperse the offending proteins could take decades.

If we can figure out the methodology for one of these diseases, it can then be applied to many of the other neurodegenerative disorders.

Huda Y. Zoghbi

Howard Hughes Medical Institute (HHMI) investigator Huda Y. Zoghbi is using a new Collaborative Innovation Award from HHMI to pull together a team of scientists to speed up that process of drug discovery. Using their collective knowledge and expertise, the researchers will identify new genes that act as tow trucks to clear disabled proteins from the brain and get traffic moving again. “If we can figure out the methodology for one of these diseases, it can then be applied to many of the other neurodegenerative disorders,” explains Zoghbi, a researcher at the Baylor College of Medicine. “This was the inspiration behind this project.”

Zoghbi and her collaborators Juan Botas, Harry Orr, and Thomas Westbrook have outlined a high-speed plan that should allow them to quickly identify hundreds of genes that help clear these mutant proteins. Then they can identify those most likely to work by testing neurons in Petri dishes, as well as in fruit fly and mouse models of neurodegenerative diseases. The result could lead to the identification of dozens of promising new molecular pathways in a fraction of the time it would have taken if the researchers had worked independently. “Should our strategy work, we could move quickly from cells to animal models,” Zoghbi said. “When this project is completed the next phase of research would be drug trials in mice that could be taken to the human patient.”

The idea is an ambitious one. The group had planned to start small, with just a few target genes, to get enough data to apply for funding for the bigger project. That's when Zoghbi heard about HHMI's new Collaborative Innovation Awards, and her project seemed a great fit.

The funding provided by HHMI will dramatically accelerate the pace of the research. “It allows us to have a much larger sample because we are drawing on everyone's expertise,” she says. “I would say this project has been expedited from taking seven or eight years to three or four years, and it's a larger amount of work than I would have taken on.”

The team will start with spinocerebellar ataxia type 1, a neurodegenerative disease caused by the buildup of the protein, ataxin-1. As ataxin-1 accumulates, it damages specific cells in the brain, leading to loss of balance and motor coordination. As muscle control deteriorates, the patients gradually become unable to eat or breathe. “Balance and coordination don't just affect the movement of our arms and legs. They affect the way we speak, the smoothness of speech, breathing, even coordination of swallowing,” Zoghbi says. She and her colleague Orr at the University of Minnesota have spent two decades studying the disease and the gene that causes it, SCA-1.

Zoghbi was inspired to use this new high-speed approach after listening to a lecture by Westbrook, a new colleague at Baylor. Westbrook uses genome-wide screens to find genes involved in human cancer. “You are not looking at 10 genes or 100 genes. You can actually evaluate the effect of every gene in the genome on the problem you are looking at. I was really excited about that,” Zoghbi says.

Westbrook hadn't applied genome-wide screens to neurodegenerative diseases before and was eager to branch out to another research area. His library of targeted RNA molecules—called short hairpin RNAs—can attach to and shut off almost any gene. Zoghbi proposed trying out the short hairpin RNAs systematically on human nerve cells grown to express the mutant ataxin-1 protein. Her goal is to identify genes that can decrease the level of ataxin-1.

Zoghbi expects the team will find hundreds of such genes using Westbrook's method. But that's just the first step. The researchers will then make sure the genes decrease ataxin-1 levels in animal models the same way they do in cell cultures. From the remaining genes, the team will pick out those that can be most easily targeted with a drug. Zoghbi quickly thought of her long-time collaborators to help in this sorting process. Botas, also at Baylor, has developed many models of human disorders in the fruit fly Drosophila. , and Orr works with disease models in mice.

Botas has already created a fruit fly that expresses the mutant human ataxin-1 protein and shows neuronal degeneration and many other key features of the human disease. Together, Orr and Zoghbi have created a mouse model that has high levels of the mutant ataxin-1 and exhibits balance problems. If shutting down the genes reverses neurodegeneration in both model organisms, the team will then look for compounds that shut down those genes.

“We are hoping that when we do the screen we will get hundreds of targets,” Zoghbi said. “Then you narrow that down to 50 or 40 or 30, and some of those will be amenable to manipulation by drugs. If you only have two or three targets to work with, then at the end of the day there may be no drug that can work for those specific targets or that drug might fail in animal trials. So having a rich pool of targets would really enhance the likelihood of success.”

In the first year, the group plans to screen ataxin-1-producing human cells using Westbrook's technique to identify the genes that reduce levels of mutant ataxin-1. In the second year, Botas will begin testing genes that interfere with ataxin-1 production in fruit flies. After that step, the rest of the team will begin secondary tests to understand the mechanism by which these genes suppress toxicity of ataxin-1. In the third and final year of the project, Orr and Zoghbi will test the candidate target genes in mice with spinocerebellar ataxia.

“You can imagine that if this works for this disease then you could try the same approach for any of the human neurodegenerative disorders where you know the culprit is a toxic protein that accumulates in neurons” Zoghbi says.

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