A neuronal CRISPRi screen identifies PQLC2 as a lysosomal pH regulator controlling tau homeostasis
Year: 2026
Type: preprint
Abstract: 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 dysregulated with aging and neurodegenerative disease, yet the mechanisms by which lysosomal pH is maintained remain incompletely understood. To better understand neuronal lysosomal pH regulation, we conducted a genome-wide CRISPRi-based screen in iPSC-derived iNeurons for modifiers of lysosomal pH. We validated several previously known regulators of lysosomal pH and identified novel pathways capable of modifying lysosomal pH, including protein UFMylation and mitochondrial homeostasis. We demonstrate that loss of the lysosomal cationic amino acid exporter, PQLC2, prevents lysosomal acidification in a manner independent of amino acid transport. A novel, tauopathy-associated mutation in PQLC2 impairs lysosomal acidification and drives tau accumulation. Together, this study reveals novel genes that modify lysosomal pH and highlights potential new targets for ameliorating age-related lysosome dysfunction.
Authors: Mackenzie Welch, Paul J. Sampognaro, Shunpan Shu, Kriti Chaplot, Anuja Bothra, Patricia A. Castruita, Andrew W. Smith, Tara Antee, Molly Hodul, Ruilin Tian, Vienna Gao, Juanita C. Limas, Kevin D. Burris, Joanne L. Parker, Jennifer S. Yokoyama, Bruce L. Miller, William W. Seeley, Simon Newstead, Martin Kampmann, Aimee W. Kao
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funder: National Institutes of Health
OpenAlex ID: W7204669400