Targeting lysosomal pH restores mitochondrial quality control in GBA1-mutant Parkinson's disease.

Overview

1. Department of Cell and Developmental Biology, University College London, UCL Consortium for Mitochondrial Research,London, WC1E 6BT UK
2. Present Address: UK Dementia Research Institute, Cardiff University,Cardiff, CF24 4HQ UK
3. Present Address: Research Centre for Molecular Medicine and Chronic Diseases (CIMUS), Research Health Institute of Santiago (IDIS), University of Santiago de Compostela,Santiago de Compostela, Spain
4. Present Address: Networking Research Centre on Neurodegenerative Diseases (CIBERNED),Madrid, Spain
5. UCL Institute of Ophthalmology,Bath Street, London, EC1V9EL UK
6. Present Address: Biofabics, Rua do Campo Lindo, Porto, Portugal
7. Department of Structural and Molecular Biology, UCL,London, WC1E 6BT UK
8. Departments of Biomedical Engineering and Chemistry, Boston University,Boston, MA 02215 USA
9. Present Address: Department of Biomedical and Chemical Engineering, Syracuse University,New York, USA
10. Department of Medicine, David Geffen School of Medicine, University of California,Los Angeles, CA 90095 USA

Abstract

Background: Heterozygous mutations in the glucocerebrosidase gene (GBA1), which encodes the lysosomal enzyme β-glucocerebrosidase (GCase), are a genetic risk factor for Parkinson’s disease (PD). The pathophysiological consequences of GBA1 mutations on dopaminergic neuronal function, especially their impact on lysosomal function, mitophagy, and mitochondrial bioenergetics, remain unclear.

Methods: Fibroblasts and dopaminergic neurons generated from induced pluripotent stem cells (iPSCs) derived from patients with GBA1-PD were used in the study. Live-cell imaging was performed to measure lysosomal acidification, protease activity, mitochondrial membrane potential, and mitophagy. Mitochondrial morphology and autophagic vesicles were examined using transmission electron microscopy. Oxygen consumption rate was measured by Seahorse assay. V-ATPase assembly was quantified using fluorescence lifetime imaging with Förster resonance energy transfer (FLIM-FRET), and pharmacological interventions included rapamycin and acidic nanoparticles.

Results: GCase activity, lysosomal acidification, protease activity, mitophagy and mitochondrial bioenergetic function were all impaired in GBA1 mutant dopaminergic neurons. Mitochondria were fragmented, with reduced membrane potential and oxygen consumption. Mechanistic target of rapamycin complex 1 (MTORC1) was constitutively phosphorylated and FLIM-FRET measurements confirmed impairment of lysosomal V-ATPase assembly, which was reversed by rapamycin treatment. Rapamycin and lysosome-targeting acidic nanoparticles rescued lysosomal pH and restored mitophagy, mitochondrial membrane potential and mitochondrial oxidative phosphorylation complex level in the GBA1 mutant dopaminergic neurons.

Conclusions: We revealed a novel mechanistic link between GBA1 mutations and mitochondrial dysfunction, as the disruption of V-ATPase assembly driven by MTORC1 activation impairs lysosomal acidification. This causes impairment of mitophagy, leading to mitochondrial dysfunction, undermining dopaminergic cell function and fate. Pharmacological intervention with rapamycin or acidic nanoparticles restores lysosomal pH and rescue mitochondrial function, representing a novel therapeutic approach for GBA1-PD .

Supplementary Information: The online version contains supplementary material available at 10.1186/s40035-026-00559-z.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

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• figshare:32723758, at figshare; found in DataCite
• figshare:32723761, at figshare; found in DataCite

Data availability

All data generated or analysed during this study are included in this published article and its supplementary information files.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 2, 28 September 2026

• Authors: added Maria Alicia Costa-Besada (0000-0002-5685-1053); Szilvia Kiraly (0009-0005-3641-5544); Kritarth Singh (0000-0003-4072-6888); Thomas S. Blacker (0000-0002-8949-6238); Orian S. Shirihai (0000-0001-8466-3431); Mark W. Grinstaff (0000-0002-5453-3668); Michael R. Duchen (0000-0003-2548-4294); removed Maria Alicia Costa-Besada; Szilvia Kiraly; Kritarth Singh; Thomas S. Blacker; Orian S. Shirihai; Mark W. Grinstaff; Michael R. Duchen

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 11 authors, 7 keywords, 11 MeSH terms, 2 funders, 78 references.

Cite

This paper

Sheshadri, P., Costa-Besada, M. A., Fisher, A., Kiraly, S., Singh, K., Kourouzidou, I., Blacker, T. S., Zeng, J., Shirihai, O. S., Grinstaff, M. W., & Duchen, M. R. (2026). Targeting lysosomal pH restores mitochondrial quality control in GBA1-mutant Parkinson's disease. Translational neurodegeneration, 15(1), 27. https://doi.org/10.1186/s40035-026-00559-z

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