A neuronal CRISPRi screen identifies PQLC2 as a lysosomal pH regulator controlling tau homeostasis

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.

Systems genetics identifies ETS1 as a stress-dependent regulator of adipocyte insulin action and heme-iron homeostasis
Y. L. Jiang, K. C. Cooke, H. B. Cutler +12
bioRxiv1 Sep 2026PreprintAll rights reservedFull textSystems & synthetic biologybioRxiv
The Alzheimer's disease risk gene ABCA7 regulates microglial lysosomal and lipid homeostasis and promotes phagocytosis to maintain neuronal health
S. E. Heuer, F. M. Ahsan, G. Terzioglu +7
bioRxiv16 Oct 2026PreprintCC BY-NCFull textNeurosciencebioRxiv
Ubiquitin ligase RNF126 exerts functions in lysosomal damage response and lysosomal homeostasis maintenance
S. Levantovsky, B. Kravic, L. Cheng +12
bioRxiv16 Oct 2026PreprintAll rights reservedFull textCell biologybioRxiv
Psychomotor disturbances in neuronal growth regulator-1-deficient (Negr1−/−) mice are associated with alterations in hippocampal and skeletal muscle signaling
Srirathi Muthuraman, Mohan Jayaram, Darja Lavogina +6
Scientific Reports20 Oct 2026Peer-reviewedCC BY-NC-ND 4.0Full textNeuroscienceCrossref
HAP40 functions as a proteostasis regulator by controlling huntingtin interactions and its release into the extracellular space
Eduardo Silva Ramos, Annett Boeddrich, Christian Haenig +22
Proceedings of the National Academy of Sciences of the United States of America22 Oct 2026Peer-reviewedCC BY 4.0Full textCell biologyPMC

Cite

BibTeX RIS

BibTeX

@misc{welch2026neuronal,
  title = {{A neuronal CRISPRi screen identifies PQLC2 as a lysosomal pH regulator controlling tau homeostasis}},
  author = {M. Welch and P. J. Sampognaro and S. Shu and K. Chaplot and A. Bothra and P. A. Castruita and A. W. Smith and T. Antee and M. Hodul and R. Tian and V. Gao and J. C. Limas and K. D. Burris and J. L. Parker and J. S. Yokoyama and B. L. Miller and W. W. Seeley and S. Newstead and M. Kampmann and A. W. Kao},
  howpublished = {bioRxiv},
  year = {2026},
  month = aug,
  doi = {10.64898/2026.08.25.747102},
  url = {https://www.biorxiv.org/content/10.64898/2026.08.25.747102v1},
  note = {CC BY},
}

RIS

TY  - UNPB
TI  - A neuronal CRISPRi screen identifies PQLC2 as a lysosomal pH regulator controlling tau homeostasis
AU  - M. Welch
AU  - P. J. Sampognaro
AU  - S. Shu
AU  - K. Chaplot
AU  - A. Bothra
AU  - P. A. Castruita
AU  - A. W. Smith
AU  - T. Antee
AU  - M. Hodul
AU  - R. Tian
AU  - V. Gao
AU  - J. C. Limas
AU  - K. D. Burris
AU  - J. L. Parker
AU  - J. S. Yokoyama
AU  - B. L. Miller
AU  - W. W. Seeley
AU  - S. Newstead
AU  - M. Kampmann
AU  - A. W. Kao
PY  - 2026
DA  - 2026/08/25
PB  - bioRxiv
DO  - 10.64898/2026.08.25.747102
UR  - https://www.biorxiv.org/content/10.64898/2026.08.25.747102v1
AB  - 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.
ER  -

Abstract

Related

Cite