Glucocerebrosidase activity in Parkinson's disease with and without GBA mutations
Glucocerebrosidase activity in Parkinson's disease with and without GBA mutations
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DOI：
10.1093/brain/awv179
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发表时间：
2015-09-01
期刊：
影响因子：
14.5
通讯作者：
Zhang, Xiaokui
中科院分区：
文献类型：
--
作者：
Alcalay, Roy N.;Levy, Oren A.;Zhang, Xiaokui
在许多研究中，葡萄糖脑苷脂酶（GBA）突变与帕金森病相关。然而，尚不清楚GBA携带者中帕金森病风险的增加是否是由于葡萄糖脑苷脂酶活性的丧失。我们测量了有和没有GBA突变的帕金森病患者（n = 517）和对照组（n = 252）的干血斑中的葡萄糖脑苷脂酶活性。参与者从纽约的哥伦比亚大学招募，并对GBA突变进行完全测序，并对LRRK 2 G2019 S突变进行基因分型，这是德系犹太人群体中最常见的常染色体显性突变。通过基于质谱的分析测量干血斑中的葡萄糖脑苷脂酶活性，并在按GBA突变状态和帕金森病诊断分类的参与者中进行比较。帕金森病患者比对照组更可能携带LRRK 2 G2019 S突变（n = 39，7.5% vs n = 2，0.8%，P50.001）和GBA突变或变异（7个纯合子和复合杂合子和81个杂合子，17.0% vs 17个杂合子，6.7%，P50.001）。GBA纯合子/复合杂合子的酶活性低于GBA杂合子（0.85 mmol/l/h vs 7.88 mmol/l/h，P50.001），GBA杂合子的酶活性低于GBA和LRRK 2非携带者（7.88 mmol/l/h vs 11.93 mmol/l/h，P50.001）。当独立比较每个突变时，与非携带者相比，杂合子的葡萄糖脑苷脂酶活性降低（N370 S，P50.001; L444 P，P50.001; 84 GG，P = 0.003; R496 H，P = 0.018），与帕金森病风险相关但与戈谢病无关的GBA变异也减少（E326K，P = 0.009; T369M，P50.001）。当考虑所有帕金森病患者时，他们的平均葡萄糖脑苷脂酶活性低于对照组（11.14 mmol/l/h vs 11.85 mmol/l/h，P = 0.011）。与对照组相比，特发性帕金森病患者（排除所有GBA和LRRK 2携带者后; 11.53 mmol/l/h vs 12.11 mmol/l/h，P = 0.036）和调整年龄和性别后（P = 0.012）的差异持续存在。有趣的是，LRRK 2 G2019 S携带者（n = 36），其中大多数患有帕金森病，具有比非携带者更高的酶活性（13.69 mmol/l/h对11.93 mmol/l/h，P = 0.002）。在特发性帕金森病患者中，在调整模型中，较高的葡萄糖脑苷脂酶活性与较长的疾病持续时间相关（P = 0.002），表明病程较轻。我们得出结论，较低的葡萄糖脑苷脂酶活性与GBA突变密切相关，与特发性帕金森病中度相关。GBA突变携带者和无GBA突变的帕金森病患者中葡萄糖脑苷脂酶活性降低的相关性表明，葡萄糖脑苷脂酶功能的丧失有助于帕金森病的发病机制。LRRK 2 G2019 S载体中的高葡萄糖脑苷脂酶活性可能反映了不同的致病机制。总之，这些数据表明，葡萄糖脑苷脂酶的酶活性可能是一个可修改的治疗目标。
Glucocerebrosidase (GBA) mutations have been associated with Parkinson's disease in numerous studies. However, it is unknown whether the increased risk of Parkinson's disease in GBA carriers is due to a loss of glucocerebrosidase enzymatic activity. We measured glucocerebrosidase enzymatic activity in dried blood spots in patients with Parkinson's disease (n = 517) and controls (n = 252) with and without GBA mutations. Participants were recruited from Columbia University, New York, and fully sequenced for GBA mutations and genotyped for the LRRK2 G2019S mutation, the most common autosomal dominant mutation in the Ashkenazi Jewish population. Glucocerebrosidase enzymatic activity in dried blood spots was measured by a mass spectrometrybased assay and compared among participants categorized by GBA mutation status and Parkinson's disease diagnosis. Parkinson's disease patients were more likely than controls to carry the LRRK2 G2019S mutation (n = 39, 7.5% versus n = 2, 0.8%, P50.001) and GBA mutations or variants (seven homozygotes and compound heterozygotes and 81 heterozygotes, 17.0% versus 17 heterozygotes, 6.7%, P50.001). GBA homozygotes/compound heterozygotes had lower enzymatic activity than GBA heterozygotes (0.85 mmol/l/h versus 7.88 mmol/l/h, P50.001), and GBA heterozygotes had lower enzymatic activity than GBA and LRRK2 non-carriers (7.88 mmol/l/h versus 11.93 mmol/l/h, P50.001). Glucocerebrosidase activity was reduced in heterozygotes compared to non-carriers when each mutation was compared independently (N370S, P50.001; L444P, P50.001; 84GG, P = 0.003; R496H, P = 0.018) and also reduced in GBA variants associated with Parkinson's risk but not with Gaucher disease (E326K, P = 0.009; T369M, P50.001). When all patients with Parkinson's disease were considered, they had lower mean glucocerebrosidase enzymatic activity than controls (11.14 mmol/l/h versus 11.85 mmol/l/h, P = 0.011). Difference compared to controls persisted in patients with idiopathic Parkinson's disease (after exclusion of all GBA and LRRK2 carriers; 11.53 mmol/l/h, versus 12.11 mmol/l/h, P = 0.036) and after adjustment for age and gender (P = 0.012). Interestingly, LRRK2 G2019S carriers (n = 36), most of whom had Parkinson's disease, had higher enzymatic activity than non-carriers (13.69 mmol/l/h versus 11.93 mmol/l/h, P = 0.002). In patients with idiopathic Parkinson's, higher glucocerebrosidase enzymatic activity was associated with longer disease duration (P = 0.002) in adjusted models, suggesting a milder disease course. We conclude that lower glucocerebrosidase enzymatic activity is strongly associated with GBA mutations, and modestly with idiopathic Parkinson's disease. The association of lower glucocerebrosidase activity in both GBA mutation carriers and Parkinson's patients without GBA mutations suggests that loss of glucocerebrosidase function contributes to the pathogenesis of Parkinson's disease. High glucocerebrosidase enzymatic activity in LRRK2 G2019S carriers may reflect a distinct pathogenic mechanism. Taken together, these data suggest that glucocerebrosidase enzymatic activity could be a modifiable therapeutic target.