A neuronal CRISPRi screen identifies PQLC2 as a lysosomal pH regulator controlling tau homeostasis
Lysosomes make key contributions to the maintenance of cellular proteostasis, and their functional compromise has been linked to aging and neurodegenerative disease. A defining characteristic of lysosomes is their relative acidity compared to other subcellular compartments, a quality that enables the efficient breakdown of macromolecules. Evidence suggests that neuronal lysosomal pH becomes…
Lysosomes, key players in cellular proteostasis, maintain their relative acidity which aids in the efficient breakdown of macromolecules. In aging and neurodegenerative diseases, neuronal lysosomal pH is often found to be dysregulated, yet the mechanisms behind lysosomal pH regulation are not fully understood. To explore this further, researchers performed a genome-wide CRISPRi-based screen in iPSC-derived iNeurons to identify modifiers of lysosomal pH.
Several known regulators of lysosomal pH were validated, and new pathways were identified that can alter lysosomal pH, such as protein UFMylation and mitochondrial homeostasis.
The study pinpointed the lysosomal cationic amino acid exporter, PQLC2, as a crucial factor in lysosomal acidification, independent of its role in amino acid transport. Moreover, a tauopathy-associated mutation in PQLC2 was found to impair lysosomal acidification and lead to tau accumulation. The findings shed light on novel genes that influence lysosomal pH and suggest potential new targets for addressing age-related lysosome dysfunction.
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