2024 Alzheimer's Association Research Fellowship (AARF)
Modeling Tdp-43 dependent Stmn2 misprocessing to study Alzheimer's disease and Frontotemporal dementia
Can preventing loss of a specific protein be a therapeutic strategy for treating Alzheimer’s?
Sarah Pickles, Ph.D.
Mayo Clinic Jacksonville
Jacksonville, FL - 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 Alzheimer’s and other dementias such as frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease). Studies have shown that about half of individuals with Alzheimer’s have elevated levels of TDP-43 in their brains and increases in TDP-43 may be linked to brain shrinkage and cognitive decline. However, the mechanisms by which TDP-43 contributes to cognitive decline in Alzheimer’s are unknown.
In healthy brain cells, TDP-43 is present in the nucleus (the control center of the cell), while in Alzheimer’s and other brain diseases, TDP-43 is present in the cytoplasm (the open, fluid-filled space inside a cell) where it accumulates in harmful clumps. Research has shown that TDP-43 accumulation in the cytoplasm can lead to abnormal splicing (a cellular process by which different regions of a gene are expressed to produce multiple proteins from a single gene) and loss of Stathmin-2 (Stmn2), a protein that is essential for nerve cell communication in the brain. Dr. Sarah Pickles and colleagues hypothesize that restoring STMN2 may be a potential treatment option to overcome the harmful effects of TDP-43 build-up in Alzheimer’s and other brain diseases.
Research Plan
For their studies, Dr. Pickles and the team will first evaluate the impact of loss of TDP-43 and loss of Stmn2 on cognitive function. They will do this by performing cognitive and behavioral assessments in genetically engineered mice that 1) do or do not have functional TDP-43 and 2) do or do not have functional Stmn2. Next, the researchers will assess whether treatment with U7 snRNA, a specialized short RNA molecule (ribonucleic acid, which carries the genetic code from the genes in your DNA to the machinery for making proteins) that can prevent abnormal splicing, in mice can restore Smnt2 function in brain cells.
Impact
This project may identify a new potential therapeutic strategy to prevent or reverse the harmful effects of TDP-43 accumulation in the brain. If successful, the results may also support future research into the use of U7 snRNA for the treatment of Alzheimer’s and other dementias.