Reid Suzanne J, Rees Mark I, van Roon-Mom Willeke M C, Jones A Lesley, MacDonald Marcy E, Sutherland Greg, During Matthew J, Faull Richard L M, Owen Michael J, Dragunow Mike, Snell Russell G
Department of Molecular Medicine, University of Auckland, Private Bag 92019, Auckland, New Zealand.
Neurobiol Dis. 2003 Jun;13(1):37-45. doi: 10.1016/s0969-9961(03)00014-7.
Recently, an inherited spinocerebellar ataxia (SCA17) has been attributed to polyglutamine coding expansions within the gene coding for human TATA-box binding protein (TBP). The normal repeat range is 25-42 units with patients having as few as 46 repeats. We undertook a TBP repeat length population study showing its relative stability, skewed distribution, and substantial population specific differences. To investigate the mechanism of neurodegeneration in SCA17 we have developed a cellular model expressing full-length TBP with a range of polyQ expansions. As has been found with other polyQ cellular models, insoluble intracellular inclusions form in a repeat-length-dependent manner. In addition, we have shown that the expanded TBP polyQ tract is able to interact with other overexpressed polyQ-containing proteins. Importantly, overexpression of expanded TBP results in increased Cre-dependent transcriptional activity. As TBP is required for transcription by all RNA polymerases, this may indicate a mechanism for aberrant polyQ gain of function.
最近,一种遗传性脊髓小脑共济失调(SCA17)被认为是由人类TATA框结合蛋白(TBP)编码基因内的聚谷氨酰胺编码扩增所致。正常重复范围是25 - 42个单位,患者最少有46个重复。我们进行了一项TBP重复长度的群体研究,显示出其相对稳定性、偏态分布以及显著的群体特异性差异。为了研究SCA17中神经退行性变的机制,我们构建了一个表达一系列聚谷氨酰胺扩增的全长TBP的细胞模型。正如在其他聚谷氨酰胺细胞模型中所发现的那样,不溶性细胞内包涵体以重复长度依赖的方式形成。此外,我们还表明,扩增的TBP聚谷氨酰胺片段能够与其他过表达的含聚谷氨酰胺蛋白相互作用。重要的是,扩增的TBP过表达导致Cre依赖的转录活性增加。由于所有RNA聚合酶转录都需要TBP,这可能表明了一种异常聚谷氨酰胺功能获得的机制。