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

Abstract

Significance Uncovering the genetic and cellular mechanisms of frontotemporal dementia (FTD) may lead to new therapeutic strategies. Mutations in the GRN gene are linked to FTD; the underlying cellular mechanisms are still unknown, but current research points to lysosomal dysfunction. Using the model organism Caenorhabditis elegans, we found a link between pgrn-1/GRN mutations, and sphingolipid metabolism and autophagy. We further identified small molecules that attenuated several pgrn-1/GRN phenotypes in vivo. These results offer sphingolipid metabolism as a potential mechanism contributing to FTD pathogenesis and suggest that efforts to restore sphingolipid homeostasis may be a beneficial therapeutic approach. In 2006, GRN 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 GRN deficiency has only recently begun to take shape. With no known cure or treatment available for GRN-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 GRN to a pathogenic state remain unclear. In our attempt to address these key issues, we have turned to the nematode, Caenorhabditis elegans, to model, study, and find potential therapies for GRN-deficient FTD. First, we show that the loss of the nematode GRN ortholog, pgrn-1, 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 pgrn-1 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 GRN/pgrn-1 deficiency. These compounds reverse the biochemical, cellular, and functional phenotypes of GRN deficiency. Together, our results open avenues for mechanistic and therapeutic research into the outcomes of GRN-related neurodegeneration, both genetic and molecular.