Galpern Wendy R, Lang Anthony E
Movement Disorders Center, Toronto Western Hospital, Toronto, Ontario, Canada.
Ann Neurol. 2006 Mar;59(3):449-58. doi: 10.1002/ana.20819.
Neurodegenerative diseases are often classified based on the abnormal accumulation of synuclein or tau. Traditionally, these disorders have been viewed as distinct clinical and pathological entities. However, advances in molecular genetics and protein biochemistry have shown intriguing overlaps. The most common synucleinopathy, Parkinson's disease, is characterized by extrapyramidal motor dysfunction, whereas the most common tauopathy, Alzheimer's disease, is defined by dementia. Yet there is overlap of clinical features; Parkinson's disease patients frequently have dementia, and Alzheimer's disease patients often manifest parkinsonism. Dementia with Lewy bodies exemplifies the existence of a continuum among these diseases. This overlap extends to the neuropathological findings; the pathognomonic hallmark for one set of disorders, Lewy bodies or neurofibrillary tangles, is present more often than expected in the other set. Moreover, mutations in LRRK2 known to cause parkinsonism are associated not only with dopaminergic neuronal degeneration, but also with the accumulation of synuclein, tau, neither, or both proteins. Other shared genetic features between tauopathies and synucleinopathies also exist. Finally, the known protein interactions between tau and synuclein further highlight the interface. Evidence for the intersection of tauopathies and synucleinopathies indicates the need for an updated disease classification scheme and may have important implications for therapeutic development.
神经退行性疾病通常根据突触核蛋白或tau蛋白的异常积累进行分类。传统上，这些疾病被视为不同的临床和病理实体。然而，分子遗传学和蛋白质生物化学的进展显示出有趣的重叠。最常见的突触核蛋白病——帕金森病，其特征是锥体外系运动功能障碍，而最常见的tau蛋白病——阿尔茨海默病，则以痴呆为特征。然而，临床特征存在重叠；帕金森病患者经常患有痴呆，而阿尔茨海默病患者常常表现出帕金森综合征。路易体痴呆体现了这些疾病之间存在连续性。这种重叠延伸到神经病理学发现；一组疾病的特征性标志——路易体或神经原纤维缠结，在另一组疾病中的出现频率比预期更高。此外，已知会导致帕金森综合征的LRRK2突变不仅与多巴胺能神经元变性有关，还与突触核蛋白、tau蛋白、两者均无或两者的积累有关。tau蛋白病和突触核蛋白病之间还存在其他共同的遗传特征。最后，tau蛋白和突触核蛋白之间已知的蛋白质相互作用进一步凸显了两者之间的关联。tau蛋白病和突触核蛋白病相互交叉的证据表明需要更新疾病分类方案，并且可能对治疗开发具有重要意义。
