A tiny one-celled organism may help scientists devise new treatments for Lou Gehrig’s disease, or ALS. The researchers, from Stanford and the Gladstone Institutes, reported their findings on Sunday in Nature Genetics. Co-senior author and Stanford geneticist Aaron Gitler, PhD, describes the work (subscription required) in our release:
“Even though yeast and humans are separated by a billion years of evolution, we were able to use the power of yeast genetics to identify an unexpected potential drug target for ALS,” said [Gitler], an associate professor of genetics at Stanford. “Many neurodegenerative disorders such as ALS, Parkinson’s and Alzheimer’s exhibit protein clumping or misfolding within the neurons that is thought to either cause or contribute to the conditions. We are trying to figure out why these proteins aggregate in neurons in the brain and spinal cord, and what happens when they do.”
Gitler and his colleagues, which include collaborators at the Gladstone Institutes, Robert Farese, Jr., MD, and Steve Finkbeiner, MD, PhD, knew from previous research that a protein called TDP-43 is involved in ALS. Mutating or making too much of the protein, which binds RNA, causes it to accumulate in the cytoplasm and begin to clump. The researchers found that blocking the expression of an RNA-processing protein, Dbr1, stopped the yeast cells from dying.
The effect seems due to the way the cell disposes of normally occurring RNA by-products of its protein-production line:
When the DNA is first copied, or transcribed, into RNA, the introns as well as the exons are included. But the cell quickly splices out the introns, which are released into the cytoplasm as little loops, or lariats. Dbr1, in turn, clips the loops to open them and make them accessible to the cell’s disposal system.
Blocking the production of Dbr1 causes the RNA lariats to build up in the cytoplasm. The researchers showed — by creating lariats with a binding site for a fluorescent tracking protein — that the mutant TDP-43 binds to these excess lariats rather than clumping. The effect is like using a paper towel to mop up a spill on your computer keyboard: binding to the lariats appears to keep TDP-43 from causing havoc elsewhere.
Although the scientists repeated their findings in rodent and human neurons, much research needs to be done to determine if sequestering TDP-43 is a valid therapeutic approach in human patients, they caution.