Section on Molecular Neurogenetics, Medical Genetics Branch, NHGRI, National Institutes of Health, Bethesda, MD 20892-3708, USA.
Acta Neuropathol. 2010 Nov;120(5):641-9. doi: 10.1007/s00401-010-0741-7. Epub 2010 Sep 14.
Mutations in the gene encoding the lysosomal enzyme glucocerebrosidase, known to cause Gaucher disease (GD), are a risk factor for the development of Parkinson disease (PD) and related disorders. This association is based on the concurrence of parkinsonism and GD, the identification of glucocerebrosidase mutations in cohorts with PD from centers around the world, and neuropathologic findings. The contribution of glucocerebrosidase to the development of parkinsonian pathology was explored by studying seven brain samples from subjects carrying glucocerebrosidase mutations with pathologic diagnoses of PD and/or Lewy body dementia. Three individuals had GD and four were heterozygous for glucocerebrosidase mutations. All cases had no known family history of PD and the mean age of disease onset was 59 years (range 42-77). Immunofluorescence studies on brain tissue samples from patients with parkinsonism associated with glucocerebrosidase mutations showed that glucocerebrosidase was present in 32-90% of Lewy bodies (mean 75%), some ubiquitinated and others non-ubiquitinated. In samples from seven subjects without mutations, <10% of Lewy bodies were glucocerebrosidase positive (mean 4%). This data demonstrates that glucocerebrosidase can be an important component of α-synuclein-positive pathological inclusions. Unraveling the role of mutant glucocerebrosidase in the development of this pathology will further our understanding of the lysosomal pathways that likely contribute to the formation and/or clearance of these protein aggregates.
编码溶酶体酶葡萄糖脑苷脂酶的基因突变被认为是帕金森病（PD）和相关疾病发展的风险因素。这种关联基于帕金森病和 GD 的同时发生，在世界各地的 PD 中心队列中鉴定出葡萄糖脑苷脂酶突变，以及神经病理学发现。通过研究来自携带葡萄糖脑苷脂酶突变的病理诊断为 PD 和/或路易体痴呆的受试者的七个脑样本，探索了葡萄糖脑苷脂酶对帕金森病病理发展的贡献。三名患者患有 GD，四名患者为葡萄糖脑苷脂酶突变杂合子。所有病例均无 PD 的家族史，发病平均年龄为 59 岁（范围为 42-77 岁）。对与葡萄糖脑苷脂酶突变相关的帕金森病患者脑组织样本进行免疫荧光研究表明，葡萄糖脑苷脂酶存在于 32-90%的路易体中（平均 75%），有些是泛素化的，有些是非泛素化的。在来自七个无突变的受试者的样本中，<10%的路易体呈葡萄糖脑苷脂酶阳性（平均 4%）。这些数据表明，葡萄糖脑苷脂酶可以成为 α-突触核蛋白阳性病理包涵体的重要组成部分。阐明突变葡萄糖脑苷脂酶在这种病理学发展中的作用将进一步加深我们对溶酶体途径的理解，这些途径可能有助于这些蛋白聚集体的形成和/或清除。
