2023 Alzheimer's Association Research Grant (AARG)

The Role of CYLD and its Partners in Frontotemporal Dementia

How does a novel gene impact cell survival in frontotemporal dementia and other brain diseases? 

Carol Dobson-Stone, Ph.D.
University of Sydney
Sydney, Australia

Background

Some brain diseases are difficult to distinguish from each other in the clinic because they may have similar symptoms, biological brain changes, and genetic contributions. This may be the case for frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease). Research indicates that abnormal build-up of the protein TAR DNA-binding protein 43 (TDP-43) in the brain is a hallmark of both diseases. Additionally, about half of the individuals with Alzheimer’s have an abnormal build-up of TDP-43 in their brains. Studies have shown that increases in TDP-43 may be connected to brain shrinkage due to nerve cell death and contribute to accelerated cognitive decline.

Dr. Carol Dobson-Stone and colleagues recently identified new variations in a gene named CYLD that appears to play a role in FTD and ALS. The researchers showed that CYLD interacts with other FTD and ALS genes and is involved in several biological pathways relevant to these diseases (including cell growth and cell death pathways). In addition, it was previously known that different variations in CYLD cause a skin tumor disorder (CYLD cutaneous syndrome, CCS). In CCS, reduced CYLD activity leads to tumors with inappropriate cell growth and survival, while decreased CYLD activity in FTD and ALS leads to increased cell death. Dr. Dobson-Stone and team believe that understanding CYLD in both contexts may shed light on common cell survival signals that are dysregulated in these disorders.

Research Plan

The research team will study the involvement of CYLD in FTD and ALS as well as in CCS to identify cell survival signals that are dysregulated when this gene is altered. They believe that this may help them identify proteins that could be new therapeutic targets for FTD, ALS, and other brain disorders. 

Using cells grown in laboratory dishes, the researchers will first investigate how variations in CYLD impact cell growth, cell death, and other biological changes associated with FTD and ALS. The team will then study whether and how CYLD interacts with proteins known to be involved in FTD and ALS. Finally, the researchers will identify how genes and proteins involved in cell survival and death are impacted by CYLD.  

Impact

This project may reveal new biological pathways involved in several brain diseases. The findings may lead to the identification of novel therapeutic targets for brain disorders including frontotemporal dementia, amyotrophic lateral sclerosis, and Alzheimer’s.