Moving and shaping neuronal lysosomes in Alzheimer's Disease

Yale University, New Haven CT

Investigators

Abstract

Abstract This project will define mechanisms that coordinate late endosome and lysosome functions across the extreme size and polarity of neurons. Although multiple proteins have been implicated in this process, there is a significant lack of understanding concerning how the network of proteins that control of lysosome function is integrated in support of the unique demands of neurons. This is a bottleneck to understanding the mechanisms whereby variants in genes encoding lysosome proteins contribute to multiple neurodegenerative diseases. In particular, this is a barrier to understanding the relevance of abnormal lysosome accumulations that occur within neurons that contact amyloid plaques in Alzheimer’s disease as it results in a lack of tools to modulate neuronal lysosomes for scientific and therapeutic purposes. Our proposed research will address these problems by building on extensive preliminary data related to the JIP3 and JIP4 proteins (encoded by the MAPK8IP3 and SPAG9 genes respectively). JIP3 and JIP4 control multiple aspects of lysosome function by acting as scaffolds that link lysosomes to motors and signaling proteins in order to regulate their subcellular distribution as well as the budding of vesicles from them. Our preliminary data indicates that there are major differences in the regulatory mechanisms that control the subcellular activities of JIP3 and JIP4 in neurons. We now seek to determine the basis for the compartmentalized differential activation of JIP3 and JIP4 and to use new insights into JIP3 and JIP4 regulation as tools to test the lysosomal contributions to Alzheimer’s disease pathogenesis. To this end, we will use experimentally tractable human cell lines to define fundamental relationships between JIP3, JIP4 and their regulatory proteins along with assays in human iPSCs and neurons derived from them and genetically modified mice to establish the physiological relevance of our discoveries. Through this research we aim to achieve the following goals: 1. Define pathways that differentially regulate JIP3 and JIP4-dependent control of lysosome subcellular distribution. 2. Determine mechanisms whereby JIP3 and JIP4 control signaling and vesicle budding events that control the protein composition of lysosome membranes. 3. Establish the in vivo impacts of JIP3 and JIP4-dependent processes on neuronal lysosomes with a focus on Alzheimer’s disease related proteins.