Corti Olga, Brice Alexis
Inserm U.289, Laboratoire de neurologie et thérapeutique expérimentale, Paris, France.
Med Sci (Paris). 2003 May;19(5):613-9. doi: 10.1051/medsci/2003195613.
Parkinson's disease is characterized by the progressive and selective loss of the dopaminergic neurons in the substantia nigra and the presence of ubiquitinated protein inclusions termed Lewy bodies. In the past six years, four genes involved in rare inherited forms of Parkinson's disease have been identified: mutations in the alpha-synuclein and ubiquitin carboxyterminal hydrolase L1 genes (UCH-L1) cause autosomal dominant forms, whereas mutations in the Parkin and DJ-1 genes are responsible for autosomal recessive forms of the disease. A toxic gain of function related to the ability of alpha-synuclein to assemble into insoluble amyloid fibrils may underlie neuronal cell death in parkinsonism due to alpha-synuclein gene mutations. In contrast, loss of protein function appears to be the cause of the disease in parkinsonism due to mutations in the genes encoding Parkin and UCH-L1, which are key enzymes of the ubiquitin-proteasome pathway. The presence of alpha-synuclein, Parkin and UCH-L1 in Lewy bodies suggests that dysfunction of pathways involved in protein folding and degradation is not only involved in the pathogenesis of familial Parkinson's disease, but could also play a role in the frequent sporadic form of the disease (idiopathic Parkinson's disease).
帕金森病的特征是黑质中多巴胺能神经元进行性、选择性丧失，以及存在被称为路易小体的泛素化蛋白包涵体。在过去六年中，已鉴定出四个与罕见遗传性帕金森病相关的基因：α-突触核蛋白和泛素羧基末端水解酶L1基因（UCH-L1）的突变导致常染色体显性形式，而帕金森病蛋白和DJ-1基因的突变则是该疾病常染色体隐性形式的病因。与α-突触核蛋白组装成不溶性淀粉样原纤维的能力相关的毒性功能获得，可能是α-突触核蛋白基因突变所致帕金森综合征中神经元细胞死亡的基础。相比之下，在帕金森综合征中，由于编码帕金森病蛋白和UCH-L1的基因突变（泛素-蛋白酶体途径的关键酶），蛋白质功能丧失似乎是疾病的病因。路易小体中存在α-突触核蛋白、帕金森病蛋白和UCH-L1，这表明参与蛋白质折叠和降解的途径功能障碍不仅与家族性帕金森病的发病机制有关，也可能在常见的散发性帕金森病（特发性帕金森病）中起作用。
