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October 10, 2025Open Access

Targeting Lysosomal pH Restores Mitochondrial Quality Control in GBA1-Mutant Parkinson’s Disease

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Authors

PSPreethi SheshadriMCMaria A. Costa-BesadaAFAndrew J. Fisher

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Overview

Live-cell imaging shows impaired lysosomal function and mitophagy in GBA1-PD, suggesting new therapeutic routes.

Key Points

  • GCase activity and mitochondrial bioenergetics were significantly impaired in GBA1-mutant neurons, affecting cellular health.
  • Treatment with rapamycin restored lysosomal acidification and improved both mitophagy and mitochondrial function.
  • Live-cell imaging revealed disrupted V-ATPase assembly linked to lysosomal dysfunction, contributing to mitochondrial fragmentation.
  • Pharmacological approaches targeting lysosomal pH may offer promising therapies for GBA1-related Parkinson’s disease.

Cite This Study

Sheshadri et al. (2025) studied this question.

synapsesocial.com/papers/68e861907ef2f04ca37e3f2chttps://doi.org/10.21203/rs.3.rs-7558589/v1
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Also Consider

Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context:

  1. 1Targeting Lysosomal pH Restores Mitochondrial Quality Control in GBA1-Mutant Parkinsons Disease2025
  2. 2GBA1 mutations as a role model for precision medicine in Parkinson’s disease2026
  3. 3Metabolic reprogramming and altered ATP content impair neuroprotective functions of microglia in β-glucocerebrosidase deficiency models2025
  4. 4The GBA1 K198E Variant Is Associated with Suppression of Glucocerebrosidase Activity, Autophagy Impairment, Oxidative Stress, Mitochondrial Damage, and Apoptosis in Skin Fibroblasts2024 · 2 citations
  5. 5Inhibition or genetic reduction of <i>ASAH1</i> /acid ceramidase restore α-synuclein clearance in mutant <i>GBA1</i> dopamine neurons from Parkinson’s patients2025