Grant: Project Grant

Mutations in CLN5 cause neuronal ceroid lipofuscinosis (NCL) commonly known as Batten disease. This devastating neurological disorder is linked to mutations in 13 genetically distinct genes. NCL affects all ages and ethnicities, is the most common form of childhood neurodegeneration, and is particularly prevalent in certain regions of Canada. Unfortunately, the precise functions of many of the NCL proteins are not known. Understanding a protein's function is central to being able to devise ways to target it therapeutically. Since mutations in NCL proteins result in nearly identical clinical phenotypes, they are thought to participate in the same biological pathway. Thus, studying the function of any one NCL protein is highly likely to enhance our knowledge of the neurodegenerative process, knowledge that can then be applied to all subtypes of the disease. The proposed research will study the localization and function of the CLN5 protein in the social amoeba Dictyostelium discoideum, which has emerged as an excellent model system for studying a variety of human neurological disorders, and is one of the only model organisms that contains the CLN5 gene. We will then perform a small molecule drug screen to identify compounds that suppress the effects of CLN5-deficiency in Dictyostelium and human cells to advance targeted therapy development for this currently untreatable disease. Finally, we will translate CLN5-deficiency phenotypes revealed in Dictyostelium to human cell models to enhance our understanding of NCL pathology. Recent genetic advances show a strong overlap of NCL with later onset forms of neurodegeneration, including Alzheimer's disease, Parkinson's disease, and frontotemporal dementia. Thus, this work has the potential to provide fresh new insight into the mechanisms underlying other forms of neurodegeneration, which is of paramount importance considering the aging Canadian population.