Department of Neurology, Columbia University Irving Medical Center New York, New York, USA.
Translational Sciences, Sanofi, Framingham, Massachusetts, USA.
Ann Clin Transl Neurol. 2020 Oct;7(10):1816-1830. doi: 10.1002/acn3.51164. Epub 2020 Sep 5.
Reduction in glucocerebrosidase (GCase; encoded by GBA) enzymatic activity has been linked to Parkinson's disease (PD). Here, we correlated GCase activity and PD phenotype in the Parkinson's Progression Markers Initiative (PPMI) cohort.
We measured GCase activity in dried blood spots from 1559 samples of participants in the inception PPMI cohort, collected in four annual visits (from baseline visit to Year-3). Participants (PD, n = 392; controls, n = 175) were fully sequenced for GBA variants by means of genome-wide genotyping arrays, whole-exome sequencing, whole-genome sequencing, Sanger sequencing, and RNA-sequencing.
Fifty-two PD participants (13.4%) and 13 (7.4%) controls carried a GBA variant. GBA status was strongly associated with GCase activity. Among noncarriers, GCase activity was similar between PD and controls. Among GBA p.E326K carriers (PD, n = 20; controls, n = 5), activity was significantly lower in PD carriers than control carriers (9.53 µmol/L/h vs. 11.68 µmol/L/h, P = 0.035). Glucocerebrosidase activity was moderately (r = 0.45) associated with white blood cell (WBC) count. Next, we divided the noncarriers with PD to tertiles based on WBC count-corrected enzymatic activity. Members of the lower tertile had higher MDS-Unified Parkinson's Disease Rating Scale motor score in the "off" medication examination at year-III exam. Longitudinal analyses demonstrated slight reduction of activity in samples collected earlier on in the study, likely because of longer storage time.
GCase activity is associated with GBA genotype, WBC count, and among p.E326K variant carriers, with PD status. Reduced activity may also be associated with worse phenotype but longer follow up is required to confirm this observation.
葡萄糖脑苷脂酶（GCase；由 GBA 编码）酶活性的降低与帕金森病（PD）有关。在这里，我们在帕金森病进展标志物倡议（PPMI）队列中比较了 GCase 活性与 PD 表型。
我们测量了来自 PPMI 队列起始队列的 1559 个样本的干血斑中的 GCase 活性，这些样本在四次年度访问（从基线访问到第 3 年）中收集。参与者（PD，n=392；对照组，n=175）通过全基因组基因分型阵列、外显子组测序、全基因组测序、Sanger 测序和 RNA-seq 对 GBA 变体进行了全面测序。
52 名 PD 参与者（13.4%）和 13 名（7.4%）对照组携带 GBA 变体。GBA 状态与 GCase 活性密切相关。在非携带者中，PD 和对照组之间的 GCase 活性相似。在 GBA p.E326K 携带者中（PD，n=20；对照组，n=5），PD 携带者的 GCase 活性明显低于对照组携带者（9.53µmol/L/h 与 11.68µmol/L/h，P=0.035）。GCase 活性与白细胞（WBC）计数中度相关（r=0.45）。接下来，我们根据 WBC 计数校正后的酶活性将非携带者分为 PD 三组分。在第 III 年的“停药”检查中，下三分位组的 MDS 统一帕金森病评定量表运动评分更高。纵向分析表明，在研究早期收集的样本中，活性略有下降，这可能是由于储存时间较长所致。
GCase 活性与 GBA 基因型、WBC 计数有关，在 p.E326K 变体携带者中与 PD 状态有关。活性降低也可能与更差的表型有关，但需要更长时间的随访来证实这一观察结果。
