Section on Molecular Neurogenetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Trends Mol Med. 2011 Sep;17(9):485-93. doi: 10.1016/j.molmed.2011.05.003. Epub 2011 Jul 1.
Clinical, genetic and pathological studies demonstrate that mutations in glucocerebrosidase (GBA), which encodes the lysosomal enzyme deficient in Gaucher disease (GD), are risk factors for Parkinson disease (PD) and related disorders. Some patients with GD and Gaucher carriers develop parkinsonism. Furthermore, subjects with PD have an increased frequency of GBA mutations. GBA-mutation carriers exhibit diverse parkinsonian phenotypes and have glucocerebrosidase-positive Lewy bodies. Although the mechanism for this association is unknown, we present several theories, including protein aggregation, prion transmission, lipid accumulation and impaired autophagy, mitophagy or trafficking. Each model has inherent limitations, and a second-hit mutation might be essential. Elucidation of the basis for this link will have important consequences for studying these diseases and should provide insights into lysosomal pathways and potential treatment strategies.
临床、遗传和病理学研究表明，葡糖脑苷脂酶（GBA）基因突变是帕金森病（PD）和相关疾病的风险因素，GBA 编码溶酶体酶缺乏症，导致戈谢病（GD）。一些 GD 患者和 Gaucher 携带者会发展为帕金森症。此外，PD 患者 GBA 基因突变的频率增加。GBA 突变携带者表现出不同的帕金森病表型，并具有葡糖脑苷脂酶阳性的路易体。虽然这种关联的机制尚不清楚，但我们提出了几种理论，包括蛋白质聚集、朊病毒传播、脂质积累以及自噬、线粒体自噬或运输受损。每个模型都有其内在的局限性，二次打击突变可能是必不可少的。阐明这种联系的基础将对研究这些疾病产生重要影响，并为溶酶体途径和潜在的治疗策略提供见解。
