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<p>Mutations in the glucocerebrosidase <i>GBA</i> gene, encoding the lysosomal enzyme β-glucocerebrosidase, represent the most frequent genetic risk factor for Parkinson’s disease, leading to lysosomal dysfunction, α-synuclein aggregation, and mitochondrial impairment. In this study, we investigated the therapeutic potential of GM1 ganglioside and its oligosaccharide portion (OligoGM1) in a cellular model of <i>GBA</i>-associated Parkinson’s disease, using SH-SY5Y neuroblastoma cells carrying the L444P <i>GBA</i> mutation. We observed that both GM1 and OligoGM1 reduced α-synuclein accumulation and improved cell viability. Notably, only OligoGM1 attenuated lysosomal overload and restored mitophagy. Additionally, OligoGM1 significantly prevented 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced toxicity, including lysosomal dysfunction, reactive oxidative species-overproduction, and mitochondrial energy failure, whereas GM1 failed to provide protection. These findings highlight the selective and multifaceted neuroprotective actions of OligoGM1 under both genetic conditions and environmental stress. Due to its small, hydrophilic nature and capacity to cross the blood–brain barrier, OligoGM1 emerges as a promising therapeutic candidate for <i>GBA</i>-related and potentially idiopathic forms of Parkinson’s Disease.</p> Graphical Abstract <p></p>

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GM1 oligosaccharide-mediated rescue in GBA-linked Parkinson’s disease via modulation of lysosomal and mitochondrial dysfunctions

  • 期刊论文

  • 发表日期：

    2025年6月4日

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  • Giulia Lunghi,
  • Carola Pedroli,
  • Ilaria Tagliabue,
  • Dorina Dobi,
  • Maria Grazia Ciampa,
  • Laura Mauri,
  • Laura Rouvière,
  • Alexandre Henriques,
  • Noelle Callizot,
  • Sandro Sonnino,
  • Elena Chiricozzi,
  • Maria Fazzari

摘要

Mutations in the glucocerebrosidase GBA gene, encoding the lysosomal enzyme β-glucocerebrosidase, represent the most frequent genetic risk factor for Parkinson’s disease, leading to lysosomal dysfunction, α-synuclein aggregation, and mitochondrial impairment. In this study, we investigated the therapeutic potential of GM1 ganglioside and its oligosaccharide portion (OligoGM1) in a cellular model of GBA-associated Parkinson’s disease, using SH-SY5Y neuroblastoma cells carrying the L444P GBA mutation. We observed that both GM1 and OligoGM1 reduced α-synuclein accumulation and improved cell viability. Notably, only OligoGM1 attenuated lysosomal overload and restored mitophagy. Additionally, OligoGM1 significantly prevented 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced toxicity, including lysosomal dysfunction, reactive oxidative species-overproduction, and mitochondrial energy failure, whereas GM1 failed to provide protection. These findings highlight the selective and multifaceted neuroprotective actions of OligoGM1 under both genetic conditions and environmental stress. Due to its small, hydrophilic nature and capacity to cross the blood–brain barrier, OligoGM1 emerges as a promising therapeutic candidate for GBA-related and potentially idiopathic forms of Parkinson’s Disease.

Graphical Abstract