In the first animal model of amyotrophic lateral sclerosis (ALS), developed by Dr Udai Pandey, Assistant Professor of Genetics at LSU Health Sciences Center New Orleans, Dr Pandey's lab has found in fruit flies that blocking the abnormal movement of a protein made by a mutated gene called FUS also blocks the disease process. The research is available online in the Advanced Access section of the journal Human Molecular Genetics website, posted on April 12, 2011. It will be published in an upcoming issue of the journal.
The fruit flies were engineered to carry and express a mutated human FUS gene. This mutated FUS gene has been shown to be 1 of the major causes of both familial and sporadic amyotrophic lateral sclerosis. In the fruit flies, the resulting neurodegeneration impairs their ability to walk or climb and the defect is also easily visualized in the structure of their eyes. In addition, the flies carrying the defective FUS gene demonstrate hallmarks of the human disease, such as an age-dependent degeneration of neurons, accumulation of abnormal proteins, and a decrease in life span.
Also as seen in human amyotrophic lateral sclerosis patients, the disease-causing FUS protein that's formed from the gene abnormally moves to the cytoplasm rather than staying in the cell nucleus. Dr Pandey's lab found that blocking this abnormal migration could block the disease process. All these features make the fly model a valuable resource for performing drug screens to identify drugs that could modify the effects of the mutated gene.
"These findings prompt us to look for drugs that can help in keeping the defective FUS protein in the nucleus as a potential therapeutic intervention" notes Pandey.
Dr Pandey's group found that normal FUS interacts with another major human amyotrophic lateral sclerosis-linked protein TDP-43, but mutated FUS interacts abnormally with normal TDP-43. Mutations in the TDP-43 gene have also been found to cause amyotrophic lateral sclerosis. Interestingly, these 2 amyotrophic lateral sclerosis-linked proteins do not seem to interact if trapped in the nucleus.
"Our next goal is to identify other factors such as proteins or RNA that mutant forms of FUS target so that we can get more insights into the disease mechanisms" said Nicholas Lanson Jr, an LSUHSC research associate and first author of the paper.
The Robert Packard Center for ALS at Johns Hopkins generously funded Dr Pandey's lab in developing a fruit fly model of amyotrophic lateral sclerosis.
Source: News Release
Louisiana State University Health Sciences Center
April 19, 2011