Toward an Understanding of HD and other Polyglutamine Diseases: Lessons from Flies and Fish - Given by Henry Paulson, M.D., Ph.D.

Spoke about the work of Nancy Bonini and Leslie Thompson with flies and his own work with zebra fish. Scientists are gaining information from research with flies and fish by placing polyglutamine expansions into their genes. There are a growing group of inherited neurogenerative disorder which are caused by polyglutamine expansions. All have protein aggregates. We can learn a lot about HD by modeling polyglutamine disease in the fly. Flies are short lived and cheap to maintain.

What can flies tell us about the disease mechanism and potential therapies? You can use the candidate gene approach or the genetic screening approach to try to find a gene which will modify the effect of the toxicity of the polyglutamine disease.

The major example of the candidate gene approach is the research with heat shock proteins. Heat shock protein chaperones play a role in the normal folding of protein. Every protein made has a chance of folding improperly. When this happens proteins can be accumulated in the cell. Hsp chaperones were overexpressed in the fly and it turns out that they do in fact suppress polyglutamine. The results of this research suggest that. "chaperones normally modulate polyglutamine toxicity and alter solubility properties of mutant protein. Findings may be exploited therapeutically."

The gene screening approach has also found twenty or so suppressor genes that reduce the effect of the polyglutamine expansion.

At this point we can say that this is an expanding and promising field of research. "Identified genes confirm a role for protein surveillance proteins, and also implicate transcriptional regulations, RNA processing, and nuclear transport pathways."

Zebrafish will hopefully provide other insights on the road to treatments. Congo red blocks toxicity). (it's a large chemical compound that can penetrate into amyloid compounds. Drug screening is on the horizon with the zebrafish.

In summary, "fly models, a growth industry in the field, have already identified genes/pathways involved in polyglutamine pathogenesis. Protein surveillance pathways seem to be important in disease (found in every suppressor gene thus far). Identification of the involved genes and pathways is far from over - screens are still underway. The zebrafish model may speed the delivery of genes and drugs from flies to mice ….. to humans?

Roles of Caspaces in HD - Given by Robert Friedlander, M.D.

Onset and progression of HD is closely correlated with cell death in the striatum. Cell death can occur by one of two cell mechanisms, either necrosis or apoptosis. You cannot affect necrosis but you can intervene in apoptosis. There are fourteen different caspaces. There are four basic functions. They lie dormant in the cytoplasm of the cell. Once they are activated, they can activate each other, they can cleave the structure of the cell and they can also affect neighboring cells. They go into the nucleus of the cell and activate other proteins which cut up the DNA of the cell which leads to the cell's death.

Caspace -1 is activated in Huntington's Disease and suppressing it delays onset and slows progression. He studied the R6/2 mice (the Bates mice) and found the activation of the caspace 1. A two fold increase was also found in the brains of human HD patients.

Caspace 1 is detected in a mouse model of ALS as well.

He crossed the R6/2 mouse with the M17Z line which has a caspace inhibitor in the brain. He found this cross had much less Caspace 1 than did the R6/2 mice and only slightly more than normal mice. The crossed mice did much better on the RotaRod motor performance test over time than the R6.2 mouse. He showed a video of the two mice and the difference was striking in appearance and motor performance. In addition, onset was significantly delayed and survival prolonged.

Also many receptors are downregulated in the R6/2 mice. Caspace 1 makes the cell dysfunctional even before death.

The research was also done pharmaceutically with a Caspace 1 inhibitor with similarly good results. The one used in the study is toxic for humans. He looked for a currently available drug that would be safe and he found a report about minocycline, an antibiotic, which reduces Caspace 1 in mice. The drug has been used for 30 years in humans with a record of safety. He announced that he had just heard yesterday that the FDA has approved minocycline for clinical trials with HD patients. They are going to start with an 8 week Phase II safety trial since minocycline can cause balance problems,. The dosage will Probably be 100 and 200 mg. There's a possibility that they might try 300 mg.

The abnormal Huntington protein somehow starts a toxic process in a population of neurons which activates caspaces, first 1 then 3. First there is cell dysfunction and then cell death. Caspace inhibitors could be one way to intervene in the disease process. As with others, he expressed the opinion that there will be a cocktail approach to treating HD, similar to the approach used with HIV treatment. It is time for realistic hope.

- published July 1, 2001
by Marsha Miller, Ph.D.