UCSF

Lysosomes are membrane-bound organelles that maintain cellular homeostasis by degrading intracellular waste as the endpoint of autophagic pathways. Impaired lysosomal function contributes to the disruption of proteostasis that characterizes aging and neurodegenerative diseases, and a growing body of evidence indicates that lysosomal alkalinization is a common feature of these conditions. Because lysosomal hydrolases require an acidic luminal environment for optimal activity, dysregulation of lysosomal pH is increasingly recognized as an important contributor to disease pathogenesis. Chapter 1 of this thesis reviews current understanding of lysosomal pH dysregulation in aging and neurodegeneration, with emphasis on the mechanisms underlying lysosomal alkalinization and the effects of restoring lysosomal acidity. Chapter 2 describes a phenotypic high-throughput screen that ultimately identified two novel lysosomal acidification compounds, WNK463 and WNK-IN-11, that are inhibitors to the WNK family of kinases, which had not previously been linked to lysosomal pH regulation. Collectively, this work advances our understanding of lysosomal pH dysregulation and supports lysosomal acidification as a promising therapeutic strategy for aging and neurodegenerative diseases.