Huang Shanshan, Yang Su, Guo Jifeng, Yan Sen, Gaertig Marta A, Li Shihua, Li Xiao-Jiang
Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Room 355, Atlanta, GA 30322, USA; Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430032, China.
Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Room 355, Atlanta, GA 30322, USA.
Cell Rep. 2015 Oct 6;13(1):196-208. doi: 10.1016/j.celrep.2015.08.060. Epub 2015 Sep 17.
In polyglutamine (polyQ) diseases, large polyQ repeats cause juvenile cases with different symptoms than those of adult-onset patients, who carry smaller expanded polyQ repeats. The mechanisms behind the differential pathology mediated by different polyQ repeat lengths remain unknown. By studying knockin mouse models of spinal cerebellar ataxia-17 (SCA17), we found that a large polyQ (105 glutamines) in the TATA-box-binding protein (TBP) preferentially causes muscle degeneration and reduces the expression of muscle-specific genes. Direct expression of TBP with different polyQ repeats in mouse muscle revealed that muscle degeneration is mediated only by the large polyQ repeats. Different polyQ repeats differentially alter TBP's interaction with neuronal and muscle-specific transcription factors. As a result, the large polyQ repeat decreases the association of MyoD with TBP and DNA promoters. Our findings suggest that specific alterations in protein interactions by large polyQ repeats may account for the unique pathology in juvenile polyQ diseases.
在多聚谷氨酰胺(polyQ)疾病中,较长的多聚谷氨酰胺重复序列导致青少年患者出现与成年发病患者不同的症状,成年发病患者携带的多聚谷氨酰胺重复序列扩展程度较小。不同长度的多聚谷氨酰胺重复序列介导的差异病理学背后的机制尚不清楚。通过研究脊髓小脑共济失调17型(SCA17)的基因敲入小鼠模型,我们发现TATA盒结合蛋白(TBP)中的一个大的多聚谷氨酰胺(105个谷氨酰胺)优先导致肌肉变性并降低肌肉特异性基因的表达。在小鼠肌肉中直接表达具有不同多聚谷氨酰胺重复序列的TBP表明,肌肉变性仅由大的多聚谷氨酰胺重复序列介导。不同的多聚谷氨酰胺重复序列以不同方式改变TBP与神经元和肌肉特异性转录因子的相互作用。结果,大的多聚谷氨酰胺重复序列减少了MyoD与TBP和DNA启动子的结合。我们的研究结果表明,大的多聚谷氨酰胺重复序列引起的蛋白质相互作用的特定改变可能是青少年多聚谷氨酰胺疾病独特病理学的原因。