Alcalay Roy N, Levy Oren A, Waters Cheryl C, Fahn Stanley, Ford Blair, Kuo Sheng-Han, Mazzoni Pietro, Pauciulo Michael W, Nichols William C, Gan-Or Ziv, Rouleau Guy A, Chung Wendy K, Wolf Pavlina, Oliva Petra, Keutzer Joan, Marder Karen, Zhang Xiaokui
1 Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA 2 Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA
1 Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA 2 Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.
Brain. 2015 Sep;138(Pt 9):2648-58. doi: 10.1093/brain/awv179. Epub 2015 Jun 27.
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 spectrometry-based 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%, P < 0.001) and GBA mutations or variants (seven homozygotes and compound heterozygotes and 81 heterozygotes, 17.0% versus 17 heterozygotes, 6.7%, P < 0.001). GBA homozygotes/compound heterozygotes had lower enzymatic activity than GBA heterozygotes (0.85 µmol/l/h versus 7.88 µmol/l/h, P < 0.001), and GBA heterozygotes had lower enzymatic activity than GBA and LRRK2 non-carriers (7.88 µmol/l/h versus 11.93 µmol/l/h, P < 0.001). Glucocerebrosidase activity was reduced in heterozygotes compared to non-carriers when each mutation was compared independently (N370S, P < 0.001; L444P, P < 0.001; 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, P < 0.001). When all patients with Parkinson's disease were considered, they had lower mean glucocerebrosidase enzymatic activity than controls (11.14 µmol/l/h versus 11.85 µmol/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 µmol/l/h, versus 12.11 µmol/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 µmol/l/h versus 11.93 µmol/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.
在众多研究中，葡萄糖脑苷脂酶（GBA）突变与帕金森病相关。然而，GBA携带者患帕金森病风险增加是否归因于葡萄糖脑苷脂酶活性丧失尚不清楚。我们测量了帕金森病患者（n = 517）和对照者（n = 252）干血斑中的葡萄糖脑苷脂酶活性，这些患者和对照者有或没有GBA突变。参与者从纽约哥伦比亚大学招募，对其进行GBA突变的全序列分析，并对LRRK2 G2019S突变进行基因分型，LRRK2 G2019S突变是阿什肯纳兹犹太人群中最常见的常染色体显性突变。通过基于质谱的检测方法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之间进行比较。帕金森病患者比对照者更有可能携带LRRK2 G2019S突变（n = 39，7.5% 对 n = 2，0.8%，P < 0.001）以及GBA突变或变异（7例纯合子和复合杂合子以及81例杂合子，17.0% 对17例杂合子，6.7%，P < 0.001）。GBA纯合子/复合杂合子的酶活性低于GBA杂合子（0.85 μmol/l/h对7.88 μmol/l/h，P < 0.001），且GBA杂合子的酶活性低于GBA和LRRK2非携带者（7.88 μmol/l/h对11.93 μmol/l/h，P < 0.001）。当独立比较每个突变时，杂合子的葡萄糖脑苷脂酶活性相比于非携带者降低（N370S，P < 0.001；L444P，P < 0.001；84GG，P = 0.003；R496H，P = 0.018），且与帕金森病风险相关但与戈谢病无关的GBA变异（E326K，P = 0.009；T369M，P < 0.001）的酶活性也降低。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者（11.14 μmol/l/h对11.85 μmol/l/h，P = 0.011）。与对照者的差异在特发性帕金森病患者中持续存在（排除所有GBA和LRRK2携带者后；11.53 μmol/l/h对12.11 μmol/l/h，P = 0.036），并且在调整年龄和性别后（P = 0.012）。有趣的是，LRRK2 G2019S携带者（n = 36），其中大多数患有帕金森病，其酶活性高于非携带者（13.69 μmol/l/h对11.93 μmol/l/h，P = 0.002）。在调整后的模型中，特发性帕金森病患者中较高的葡萄糖脑苷脂酶活性与疾病持续时间较长相关（P = 0.002），提示病程较轻。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，与特发性帕金森病也有一定关联。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均较低，这表明葡萄糖脑苷脂酶功能丧失促成了帕金森病的发病机制。LRRK2 G2019S携带者中较高的葡萄糖脑苷脂酶活性可能反映了一种独特的致病机制。综上所述，这些数据表明葡萄糖脑苷脂酶活性可能是一个可调节的治疗靶点。
