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<p>Genetic variants in <i>GBA1</i>, encoding the lysosomal enzyme glucocerebrosidase (GCase), represent the strongest genetic risk factor for Parkinson’s disease (PD) and provide a mechanistic link between Gaucher disease (GD) and PD. While biallelic <i>GBA1</i> mutations cause GD, heterozygous variants confer an increased, age-dependent risk of PD, with mutation-specific differences in penetrance, age at onset, cognitive decline, and survival. This review critically examines the molecular and clinical spectrum of <i>GBA1</i>-associated PD (GBA1-PD), highlighting the relationship between variant severity, lysosomal dysfunction, and disease progression. We discuss two major, partially overlapping pathogenic frameworks underlying <i>GBA1</i>-PD: loss-of-function mechanisms associated with reduced GCase activity, glycosphingolipid accumulation, and impaired autophagy–lysosomal pathways, and toxic gain-of-function mechanisms driven by mutant GCase misfolding, endoplasmic reticulum stress, and proteostatic imbalance. Increasing evidence suggests that these mechanisms converge on α-synuclein aggregation and dopaminergic neurodegeneration. We further summarize emerging disease-modifying therapeutic strategies, including small-molecule GCase activators, pharmacological chaperones, substrate reduction therapies, acid ceramidase inhibitors, and gene therapies. Although clinical outcomes have been heterogeneous, <i>GBA1</i>-associated PD represents a valuable model for precision medicine, illustrating how genetic stratification can guide mechanism-based therapeutic development in neurodegeneration.</p>

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GBA1 mutations as a role model for precision medicine in Parkinson’s disease

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年8月4日

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  • Christiane Oleksy,
  • Ibrahim Boussaad,
  • Zied Landoulsi,
  • Mia Horowitz,
  • Rejko Krüger

摘要

Genetic variants in GBA1, encoding the lysosomal enzyme glucocerebrosidase (GCase), represent the strongest genetic risk factor for Parkinson’s disease (PD) and provide a mechanistic link between Gaucher disease (GD) and PD. While biallelic GBA1 mutations cause GD, heterozygous variants confer an increased, age-dependent risk of PD, with mutation-specific differences in penetrance, age at onset, cognitive decline, and survival. This review critically examines the molecular and clinical spectrum of GBA1-associated PD (GBA1-PD), highlighting the relationship between variant severity, lysosomal dysfunction, and disease progression. We discuss two major, partially overlapping pathogenic frameworks underlying GBA1-PD: loss-of-function mechanisms associated with reduced GCase activity, glycosphingolipid accumulation, and impaired autophagy–lysosomal pathways, and toxic gain-of-function mechanisms driven by mutant GCase misfolding, endoplasmic reticulum stress, and proteostatic imbalance. Increasing evidence suggests that these mechanisms converge on α-synuclein aggregation and dopaminergic neurodegeneration. We further summarize emerging disease-modifying therapeutic strategies, including small-molecule GCase activators, pharmacological chaperones, substrate reduction therapies, acid ceramidase inhibitors, and gene therapies. Although clinical outcomes have been heterogeneous, GBA1-associated PD represents a valuable model for precision medicine, illustrating how genetic stratification can guide mechanism-based therapeutic development in neurodegeneration.