Therapeutic potential of cAMP-mediated lysosomal pH modulation in ATP6V1B2-related neuropathology.

Authors

Lu Zheng, Weihao Zhao, Guang Yang, Shiwei Qiu, Yahong Li, Lin Gao, Gege Wei, Ying Ma, Jiangping Xie, Xue Gao, Linyan Chen, Xiaoge Li, Rongfeng Lin, Wei Xiong, Yongyi Yuan, Pu Dai

Published in

Cell death discovery. Volume 12. Issue 1. Mar 27, 2026. Epub Mar 27, 2026.

Abstract

Pathogenic variants in ATP6V1B2, which encodes a critical subunit of vacuolar-type H+-ATPases (V-ATPases), disrupt lysosomal acidification via haploinsufficiency and clinically manifest as intellectual disability and seizure disorders. Despite significant morbidity, mechanism-based therapies remain an unmet need. Through integrated clinical analysis of a Chinese cohort and systematic literature review, we delineated genotype-phenotype correlations in ATP6V1B2-related syndromes. Isogenic HEK293T models (ATP6V1B2^R506X/+ and ATP6V1B2^R506X/R506X) were generated using CRISPR/Cas9 for dynamic lysosomal pH monitoring via ratiometric RpH-LAMP1-3×flag imaging to evaluate pathophysiological mechanisms. Parallel investigations in Atp6v1b2^R506X/R506X mice incorporated continuous video-EEG monitoring, behavioral assessments, western blot analyses, and transmission electron microscopy to evaluate therapeutic responses. Drug concentrations in plasma and brain homogenates were quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Clinical analysis revealed central nervous system manifestations (epilepsy, intellectual disability, developmental delay) as primary morbidity determinants. Cellular studies demonstrated significant increase of lysosomal pH in mutant cells compared to wild-type control. Remarkably, treatment with the cAMP analog CPT-cAMP restored lysosomal acidification in a concentration-dependent manner. In vivo studies confirmed spontaneous seizure activity in mutant mice and CPT-cAMP's penetration of the BBB was confirmed by LC-MS/MS. Intraperitoneal CPT-cAMP administration (20 mg/kg) exerted triple therapeutic effects: (1) significant reduction in seizure frequency, (2) improved cognitive performance in behavioral paradigms, and (3) restoration of autophagic flux through resolution of autophagosome accumulation. These findings establish proof-of-concept for cAMP-mediated lysosomal pH modulation as a viable therapeutic strategy. Our results position CPT-cAMP as a promising candidate for addressing both neurological and cognitive manifestations in ATP6V1B2-related disorders.

PMID:
41896517
Bibliographic data and abstract were imported from PubMed on 14 Sep 2026.

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