Validation of PIKFYVE Inhibition as a Therapeutic Approach for Diverse Forms of Frontotemporal Dementia
Abstract
This application addresses the need for new therapeutic approaches for frontotemporal degeneration, or frontotemporal dementia (FTD). FTD is a fatal neurodegenerative disease and is the most common cause of dementia in people under 60. FTD affects veterans, members of the military, and its incidence is increased with traumatic brain injury. Unfortunately, there are no treatments that slow the progression of FTD. Genetic studies have shown that there are many different genetic causes of FTD, with each cause accounting for only a small fraction of cases. Although it may be possible to design individual therapies for each form of FTD, this will take decades to develop and this approach will not address the majority of FTD cases that are not caused by the known genetic mutations. Thus, there is a pressing need for new therapeutic strategies that rescue multiple forms of FTD, including those with unknown genetic causes. We reasoned that if we could test many drugs and drug-like molecules on nerve cells from different FTD patients in the petri dish, we would identify drug targets that reverse the degeneration of nerve cells across multiple forms of FTD. Naturally, it is difficult to obtain nerve cells from living patients safely, so we used a technology called cellular reprogramming to generate nerve cells from blood cells of FTD patients. Once we made these nerve cells, we found that they mimicked the behavior of nerve cells within FTD patients, including rapid degeneration and the accumulation of specific proteins that aggregate and cause nerve cell death. We tested 2000 FDA approved drugs and 1800 drug-like molecules for the ability to reverse the degeneration of nerve cells from different FTD patients. From this screen, we identified inhibitors of a protein called PIKFYVE as the most potent rescuers of nerve cell survival from multiple FTD patients. Inhibitors of PIKFYVE have never been tested before for neurodegenerative diseases, although some groups are developing PIKFYVE inhibitors for autoimmune diseases and cancer. Our preliminary studies show that PIKFYVE inhibition not only extends the survival of FTD patient nerve cells in the petri dish, but it also reduces disease symptoms in mice carrying FTD-causing mutations. In addition, PIKFYVE inhibition reverses the accumulation of the protein aggregates that cause nerve cell death in FTD in both the petri dish and mice. Surprisingly, PIKFYVE inhibition seems to rescue neurodegeneration by transiently blocking the typical way in which nerve cells degrade toxic protein aggregates, a process called autophagy. Autophagy is conceptually similar to a garbage disposal that breaks up unwanted proteins into small pieces that can be reused as building blocks for new proteins. We would have predicted that blocking autophagy would accelerate nerve cell death. However, we find that blocking autophagy triggers the nerve cells to remove the proteins aggregates by secreting them. This process, called secretory autophagy, turns out to be much more efficient at eliminating the protein aggregates from nerve cells than normal autophagy. Secretory autophagy has only recently been shown to take place in animals, and it remains unclear if there are ways to activate it and leverage it to protect against neurodegeneration. The goal of our study is to confirm that PIKFYVE inhibition reverses nerve cell death in FTD by testing PIKFYVE inhibition on nerve cells from more FTD patients and FTD mouse models. In addition, we will verify that PIKFYVE inhibition reverses FTD nerve cell death by inducing secretory autophagy. If successful, our proposed study will establish PIKFYVE inhibition and secretory autophagy as critical therapeutic targets for FTD.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110168
Entities
People
- Justin K Ichida
Organizations
- United States Army
- University of Southern California