Mutations in GBA1, the gene encoding the lysosomal enzyme glucocerebrosidase, are among the most common known genetic risk factors for the development of Parkinson disease and related synucleinopathies. A great deal is known about GBA1, as mutations in GBA1 are causal for the rare autosomal storage disorder Gaucher disease. Over the past decades, significant progress has been made in understanding the genetics and cell biology of glucocerebrosidase. A least 495 different mutations, found throughout the 11 exons of the gene are reported, including both common and rare variants. Mutations in GBA1 may lead to degradation of the protein, disruptions in lysosomal targeting and diminished performance of the enzyme in the lysosome.Gaucher disease is phenotypically diverse and has both neuronopathic and non-neuronopathic forms. Both patients with Gaucher disease and heterozygous carriers are at increased risk of developing Parkinson disease and Dementia with Lewy Bodies, although our understanding of the mechanism for this association remains incomplete. There appears to be an inverse relationship between glucocerebrosidase and α-synuclein levels, and even patients with sporadic Parkinson disease have decreased glucocerebrosidase. Glucocerebrosidase may interact with α-synuclein to maintain basic cellular functions, or impaired glucocerebrosidase could contribute to Parkinson pathogenesis by disrupting lysosomal homeostasis, enhancing endoplasmic reticulum stress or contributing to mitochondrial impairment. However, the majority of patients with GBA1 mutations never develop parkinsonism, so clearly other risk factors play a role. Treatments for Gaucher disease have been developed that increase visceral glucocerebrosidase levels and decrease lipid storage, although they have yet to properly address the neurological defects associated with impaired glucocerebrosidase. Mouse and induced pluripotent stem cell derived models have improved our understanding of glucocerebrosidase function and the consequences of its deficiency. These models have been used to test novel therapies including chaperone proteins, histone deacetylase inhibitors, and gene therapy approaches that enhance glucocerebrosidase levels and could prove efficacious in the treatment of forms of parkinsonism. Consequently, this rare monogenic disorder, Gaucher disease, provides unique insights directly applicable to our understanding and treatment of Parkinson disease, a common and complex neurodegenerative disorder.

中文翻译：

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葡萄糖脑苷脂酶及其与帕金森氏病的相关性。

GBA1（编码溶酶体酶葡萄糖脑苷脂酶的基因）中的突变是帕金森氏病和相关突触核蛋白病发展的最常见的已知遗传危险因素之一。有关GBA1的信息很多，因为GBA1中的突变是罕见的常染色体贮积病高雪氏病的病因。在过去的几十年中，在了解葡萄糖脑苷脂酶的遗传学和细胞生物学方面取得了重大进展。据报道，在该基因的11个外显子中至少发现了495个不同的突变，包括常见和罕见变体。GBA1中的突变可能导致蛋白质降解，溶酶体靶向破坏和溶酶体中酶的性能下降。高雪氏病在表型上是多样的，既有神经病性疾病也有非神经元性疾病。尽管我们对这种关联机制的理解仍不完全，但患有高雪氏病和杂合子携带者的患路易氏体的帕金森病和痴呆症的患病风险均增加。葡糖脑苷脂酶与α-突触核蛋白水平之间似乎存在反比关系，甚至偶发性帕金森病患者的葡糖脑苷脂酶含量也降低。葡萄糖脑苷脂酶可能与α-突触核蛋白相互作用以维持基本的细胞功能，或者受损的葡萄糖脑苷脂酶可能通过破坏溶酶体稳态，增强内质网应激或导致线粒体损伤而促进帕金森病的发病。但是，大多数具有GBA1突变的患者从未发展为帕金森氏症，因此显然其他危险因素也起作用。已经开发了用于治疗高雪氏病的疗法，其可以增加内脏葡萄糖脑苷脂酶的水平并减少脂质的储存，尽管它们尚不能适当地解决与葡萄糖脑苷脂酶受损有关的神经系统缺陷。小鼠和诱导性多能干细胞衍生模型改善了我们对葡萄糖脑苷脂酶功能及其缺乏后果的理解。这些模型已用于测试新型疗法，包括伴侣蛋白，组蛋白脱乙酰基酶抑制剂和增强葡萄糖脑苷脂酶水平并可能在治疗帕金森氏症方面有效的基因治疗方法。因此，这种罕见的单基因疾病高雪氏病提供了独特的见解，可直接应用于我们对帕金森氏病的理解和治疗，