Evaluation of TFAP4 regulation of lysosome biogenesis and modulation of tau pathology

Yale University, New Haven CT

Investigators

Abstract

PROJECT SUMMARY Millions of individuals are afflicted with Alzheimer’s disease and related tauopathies, and with our aging population, the occurrence of these devastating diseases will continue to increase, posing an immense burden on our healthcare system. Tauopathies are marked by the accumulation of toxic tau species leading to progressive neuron loss. Impairments in the autophagy-lysosome pathway (ALP), an essential cellular process used to clear waste, recycle resources, and maintain homeostasis, have been reported across neurodegenerative diseases contributing to the build-up of toxic protein species. Strategies to promote the activity of the ALP could prevent the formation or enhance the clearance of these inclusions and offer therapeutic benefits for many neurodegenerative diseases including tauopathies where there is a need for effective treatment options. Our lab recently found nemo-like kinase acts as a negative regulator of the lysosome and that reduction of the protein is able to ameliorate neurodegenerative phenotypes. Upon further investigation into this signaling pathway, we identified TFAP4 as a potential transcriptional regulator of lysosome biogenesis and function. In vitro studies revealed TFAP4 overexpression was able to increase transcription of genes belonging to the coordinated lysosomal enhancement and regulation (CLEAR) network, increase levels of lysosome-associated proteins, increase lysosome number and size, and increase lysosomal hydrolytic activity. For this proposal, we generated cell-type specific Cre-inducible TFAP4 overexpression and knock-out mice that will allow us to evaluate the role of TFAP4 towards lysosome biogenesis and function in healthy and diseased neuronal populations in vivo. Specific aim 1 will be used to better understand the molecular mechanisms underlying TFAP4 activity through the use of molecular, biochemical, histological, and transcriptomic approaches to confirm lysosomal alterations in vivo and identify the gene targets of TFAP4. Specific aim 2 will allow us to evaluate the therapeutic potential of TFAP4 modulation using a tauopathy mouse model where we will look for pathological changes including alterations in hyperphosphorylated tau, neurofibrillary tangle formation, and synapse number as well as behavioral changes in cognition and working memory. The completion of these research aims in combination with my proposed training plan will provide me with a strong foundation to embark on a career as an independent researcher investigating the mechanisms underlying neurodegeneration.