<< Back
Can an RNA therapy prevent or reverse the build-up of an abnormal protein in brain cells?
James Shorter, Ph.D.
University of Pennsylvania
Philadelphia, PA - United States
Background
Abnormal build-up of the protein TAR DNA-binding protein 43 (TDP-43) in the brain is a hallmark of many brain diseases, including frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease). Additionally, about half of the individuals with Alzheimer’s have an abnormal build-up of TDP-43 in their brains. Research suggests that increases in TDP-43 may be linked to brain shrinkage and cognitive decline in individuals with Alzheimer’s and other diseases that cause dementia.
Studies have shown that the accumulation of TDP-43 results, in part, from a biological process called phase separation. This process separates TDP-43 molecules into droplet-like structures, which can clump together in brain cells. In Alzheimer’s, ALS, and other brain diseases, TDP-43 moves from the nuclei (the control center of the cell) of brain cells and into the cytoplasm (the open area of the cell), where it may accumulate in harmful clumps.
Dr. James Shorter and colleagues will investigate a therapy that reverses the abnormal accumulation of TDP-43 in the cytoplasm and returns the protein to its typical form in the nucleus. The researchers have discovered short, specific molecules of RNA (ribonucleic acid, which carries the genetic code from the genes in your DNA to the machinery for making proteins) that prevent and reverse abnormal phase separation of TDP-43 in cells grown in laboratory dishes.
Research Plan
Dr. Shorter and colleagues will generate and optimize short RNAs that reverse TDP-43 accumulation and restore TDP-43 to the nucleus in patient-derived brain cells and in mice.
Out of 150 short RNAs that the team screened, they selected two lead molecules that prevent and reverse abnormal TDP-43 phase separation. The researchers will optimize these RNAs to enhance TDP-43 binding and reduce off-target effects.
The researchers will test whether these short RNAs can protect human nerve cells in laboratory dishes from abnormal TDP-43 phase separation. They will use a specialized technique called optogenetics, which involves directing precisely controlled pulses of light at specific cells to stimulate their activity. The team will treat nerve cells with RNAs before or after stimulating abnormal phase separation to track whether RNAs can prevent or reverse this process.
Dr. Shorter and colleagues will also test the lead RNAs in mice genetically engineered to develop TDP-43 accumulation in their brains. They will use a modified virus to deliver RNAs to the central nervous system in the mice and assess the effects of the treatment.
Impact
If successful, this project may identify a potential therapy to prevent or reverse the accumulation of a harmful protein in the brain. The results may support further investigations of short RNAs for the prevention or treatment of brain diseases including Alzheimer’s.
Back to Top