Chemical and genetic rescue of in vivo progranulin-deficient lysosomal and autophagic defects.

Abstract

In 2006, <i>GRN</i> mutations were first linked to frontotemporal dementia (FTD), the leading cause of non-Alzheimer dementias. While much research has been dedicated to understanding the genetic causes of the disease, our understanding of the mechanistic impacts of <i>GRN</i> deficiency has only recently begun to take shape. With no known cure or treatment available for <i>GRN</i>-related FTD, there is a growing need to rapidly advance genetic and/or small-molecule therapeutics for this disease. This issue is complicated by the fact that, while lysosomal dysfunction seems to be a key driver of pathology, the mechanisms linking a loss of <i>GRN</i> to a pathogenic state remain unclear. In our attempt to address these key issues, we have turned to the nematode, <i>Caenorhabditis elegans</i>, to model, study, and find potential therapies for <i>GRN</i>-deficient FTD. First, we show that the loss of the nematode <i>GRN</i> ortholog, <i>pgrn-1</i>, results in several behavioral and molecular defects, including lysosomal dysfunction and defects in autophagic flux. Our investigations implicate the sphingolipid metabolic pathway in the regulation of many of the in vivo defects associated with <i>pgrn-1</i> loss. Finally, we utilized these nematodes as an in vivo tool for high-throughput drug screening and identified two small molecules with potential therapeutic applications against <i>GRN</i>/<i>pgrn-1</i> deficiency. These compounds reverse the biochemical, cellular, and functional phenotypes of <i>GRN</i> deficiency. Together, our results open avenues for mechanistic and therapeutic research into the outcomes of <i>GRN</i>-related neurodegeneration, both genetic and molecular.