Understanding Lysosome Dysfunction in Alzheimer's Disease

The health and survival of neurons in the brain is dependent on a recycling pathway carried out by lysosomes, cellular organelles that help degrade and recycle proteins. Defects in the function of lysosomes are increasingly thought to be involved in the development of Alzheimer’s disease (AD). We are trying to understand why decreases in a protein called progranulin impair lysosome function and increase the risk of developing Alzheimer’s disease. This research will help our long-term effort to develop drugs to treat Alzheimer’s disease by correcting lysosome function.

Increasing evidence suggest that dysfunction of lysosomes, a critical component within cells, plays a key role in the development of Alzheimer’s disease (AD). The health and survival of neurons in the brain is dependent on lysosomes, cellular organelles that help degrade and recycle proteins. We are trying to understand why decreases in a protein called progranulin impair lysosome function and increase the risk of developing AD. This research project will help our long-term effort to develop drugs to treat AD by correcting or boosting lysosome function to prevent neurodegeneration.

This research proposal focuses on the role of endosome-lysosome dysfunction in AD and related dementias, such as frontotemporal dementia (FTD). Mutations or SNPs in the GRN gene, which encodes the progranulin (PGRN) protein, increase the risk of developing AD or FTD by decreasing the levels of PGRN.  We have discovered that PGRN is trafficked to the lysosome and processed into stable granulin proteins (called GRNs), which we hypothesize play a key role in lysosome health and function. However, the function of GRNs is unknown. In this project, we will identify the binding partners of PGRN and GRNs in the endosomal-lysosomal network to gain insight into their function. We will also generate a transgenic (tg) TMEM192 mouse, that can be used to isolate lysosomes and will have broad utility in the AD and neurodegenerative field, because they will allow investigators to evaluate lysosome dysfunction and rescue in vivo. Further, they can immediately be used in the many AD mouse models that have already been generated to provide a deeper understanding of AD pathogenesis. Moreover, tgTMEM192 mice can be used for in vivo in and cell type or mouse model thus will have broad application to many fields beyond AD.