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<p>Variants in <i>GBA1</i>, encoding lysosomal glucocerebrosidase (GCase), are risk factors for Parkinson’s disease (PD), which is characterized by α-synuclein (αSyn) accumulation and lysosomal dysfunction. Nonetheless, the relationship between αSyn accumulation and GCase deficiency remains unclear. This study aims to quantitatively define the biochemical relationship between GCase and αSyn in GBA-related PD (GBA-PD) and idiopathic PD (IPD). Here, we sequenced <i>GBA1</i> in 160 post-mortem brains (25 iLBD, 114 PD, 21 controls) and conducted quantitative biochemical analysis of the locus coeruleus (LC), substantia nigra (SN) and gyrus temporalis medius (GTM). We measured Total, Ser129-phosphorylated (pSer129), and C-terminally-truncated αSyn proteoforms, and quantified GCase activity and protein levels. <i>GBA1</i> variants were detected in 21.9% of PD cases, including a novel frameshift variant. Cortical and midbrain αSyn burden did not differ between GBA-PD and IPD. Importantly, GCase activity and protein levels were substantially reduced in both GBA-PD and IPD across regions, while GCase specific activity was reduced only in the GBA-PD group. pSer129 αSyn burden was inversely correlated with GCase activity, both in the presence (GBA-PD) and absence (IPD) of <i>GBA1</i> variants. These findings demonstrate a biochemical link between pSer129-enriched αSyn deposition and GCase deficiency across the PD spectrum, supporting lysosomal/GCase-enhancing therapies regardless of <i>GBA1</i> status.</p>

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Quantitative biochemical profiling of GCase activity and α-synuclein proteoforms in post-mortem human brains from GBA-related and idiopathic Parkinson’s disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月5日

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  • Martino L. Morella,
  • Martha Teneketzi,
  • Federico Ferraro,
  • Tim E. Moors,
  • Walter A. Boiten,
  • John J. P. Breve,
  • Angela M. T. Ingrassia,
  • Hanneke Geut,
  • Lasse Pihlstrøm,
  • Vinod Udayar,
  • Vincenzo Bonifati,
  • Wilma D. J. van de Berg

摘要

Variants in GBA1, encoding lysosomal glucocerebrosidase (GCase), are risk factors for Parkinson’s disease (PD), which is characterized by α-synuclein (αSyn) accumulation and lysosomal dysfunction. Nonetheless, the relationship between αSyn accumulation and GCase deficiency remains unclear. This study aims to quantitatively define the biochemical relationship between GCase and αSyn in GBA-related PD (GBA-PD) and idiopathic PD (IPD). Here, we sequenced GBA1 in 160 post-mortem brains (25 iLBD, 114 PD, 21 controls) and conducted quantitative biochemical analysis of the locus coeruleus (LC), substantia nigra (SN) and gyrus temporalis medius (GTM). We measured Total, Ser129-phosphorylated (pSer129), and C-terminally-truncated αSyn proteoforms, and quantified GCase activity and protein levels. GBA1 variants were detected in 21.9% of PD cases, including a novel frameshift variant. Cortical and midbrain αSyn burden did not differ between GBA-PD and IPD. Importantly, GCase activity and protein levels were substantially reduced in both GBA-PD and IPD across regions, while GCase specific activity was reduced only in the GBA-PD group. pSer129 αSyn burden was inversely correlated with GCase activity, both in the presence (GBA-PD) and absence (IPD) of GBA1 variants. These findings demonstrate a biochemical link between pSer129-enriched αSyn deposition and GCase deficiency across the PD spectrum, supporting lysosomal/GCase-enhancing therapies regardless of GBA1 status.