Departamento de Química Física Aplicada, Universidad Autónoma de Madrid, Centro de Biología Molecular Severo Ochoa, CSIC Madrid, Spain.
J Alzheimers Dis. 2010;22(2):375-91. doi: 10.3233/JAD-2010-100189.
A number of neurodegenerative diseases, including Alzheimer's disease, tauopathies, Parkinson's disease, and synucleinopathies, polyglutamine diseases, including Huntington's disease, amyotrophic lateral sclerosis, and transmissible spongiform encephalopathy, are characterized by the existence of a protein or peptide prone to aggregation specific to the disease: amyloid-β, tau protein, α-synuclein, atrophin 1, androgen receptor, prion protein, copper-zinc superoxide dismutase, α 1A subunit of CaV2.1, TATA-box binding protein, huntingtin, and ataxins 1, 2, 3, and 7. Beside this common molecular feature, we have found three additional main properties related to the disease-connected protein or peptide, which are shared by all those neurological disorders: first, proneness to aggregation, which, in many cases, seems to be bound to the lack of a clearly defined secondary structure; second, reported presence of the disease-related protein inside the nucleus; and finally, an apparently unspecific interaction with DNA. These findings, together with the lack of clear details to explain the molecular origin of these neurodegenerative diseases, invite a hypothesis that, together with other plausible molecular explanations, may contribute to find the molecular basis of these diseases: I propose here the hypothesis that many neurological disorders may be the consequence, at least in part, of an aberrant interaction of the disease-related protein with nucleic acids, therefore affecting the normal DNA expression and giving place to a genetic stress which, in turn, alters the expression of proteins needed for the normal cellular function and regulation.
许多神经退行性疾病，包括阿尔茨海默病、tau 病、帕金森病和突触核蛋白病、多聚谷氨酰胺病，包括亨廷顿病、肌萎缩侧索硬化症和传染性海绵状脑病，其特征是存在特定于疾病的易聚集蛋白或肽：淀粉样-β、tau 蛋白、α-突触核蛋白、atrophin 1、雄激素受体、朊病毒蛋白、铜锌超氧化物歧化酶、CaV2.1 的α1A 亚基、TATA 框结合蛋白、亨廷顿蛋白和ataxins 1、2、3 和 7。除了这种常见的分子特征外，我们还发现了与疾病相关的蛋白质或肽相关的另外三个主要特性，这些特性为所有这些神经退行性疾病所共有：首先，易于聚集，在许多情况下，这似乎与缺乏明确的二级结构有关；其次，报告称疾病相关蛋白存在于细胞核内；最后，与 DNA 显然没有特异性相互作用。这些发现，加上缺乏明确的细节来解释这些神经退行性疾病的分子起源，促使我们提出一个假设，即与其他合理的分子解释一起，可能有助于找到这些疾病的分子基础：我在这里提出一个假设，即许多神经退行性疾病可能至少部分是由于疾病相关蛋白与核酸的异常相互作用引起的，从而影响正常的 DNA 表达，并导致遗传应激，进而改变正常细胞功能和调节所需蛋白质的表达。
