CFR Researchers Identify ALS and Frontotemporal Dementia Treatment Target

SAN FRANCISCO, CA – 11/6/12. Researchers in the laboratories of CFR Investigators Bob Farese, M.D. and Steven Finkbeiner, M.D., Ph.D. have identified an enzyme, Dbr1, which may be used as a therapeutic target to prevent the toxic accumulation of protein aggregates often found in the brains of patients with frontotemporal dementia and amyotrophic lateral sclerosis (ALS). Their work, which was co-authored with scientists in the laboratory of Aaron Gitler, Ph.D. at Stanford University, was published online in Nature Genetics on October 26th.

A build-up of TDP-43 is found in neurons of most patients with ALS, approximately half of all patients with frontotemporal dementia, as well as many patients with Alzheimer’s disease. Therefore, strategies that target TDP-43 hold promise as effective therapies for a broad range of neurodegenerative diseases. Normally TDP-43 is found in the nucleus where it binds RNA, but in diseased cells it aggregates in the cytoplasm and causes cells to die. Led by co-first authors Maria Armakola at Stanford and Matt Higgins, Ph.D. at the Gladstone Institutes, the authors created a yeast model that mimics key features of TDP-43 toxicity observed in human diseases.

Higgins, Armakola and teams searched for genes that enhanced or suppressed TDP-43’s toxicity in order to identify the molecular mechanisms that underpin TDP-43’s role in disease pathogenesis. They found that if they lowered the amount of Dbr1, an enzyme involved in pre-mRNA processing, then TDP-43 was no longer toxic in their yeast model or, importantly, in rat cortical neurons with TDP-43 aggregates.

“Reducing Dbr1 dramatically restored cell viability even though these cells still contained TDP-43 aggregates,” said Dr. Farese. “Dbr1 is a unique enzyme that is required for clearance of leftover products of mRNA processing called lariats. We believe that without Dbr1, these leftover lariats build-up and displace RNAs vital for cell survival that would otherwise be trapped in TDP-43 aggregates. That displacement ensures key RNAs can continue their important functions and alleviates toxicity.”

Researchers developed a novel way to track lariats and showed they do indeed serve as a sink for TDP-43. They also mutated Dbr1 to destroy its enzymatic function to varying degrees and observed that TDP-43’s toxicity was tightly linked to Dbr1’s debranching activity – more debranching caused more TDP-43 toxicity, further supporting their findings that a build-up of lariats neutralizes TDP-43’s toxicity.

These exciting findings suggest blocking Dbr1 could prove an effective therapeutic intervention in ALS, frontotemporal dementia and other diseases with TDP-43 aggregation, although much work will be needed. In particular, an important step will be to determine how much of a reduction of TDP-43 healthy cells can tolerate. Researchers can then extend these yeast studies into mammalian cells with a goal of identifying small molecules that may inhibit Dbr1.