Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy.
Department of Biology, University of Bari, Bari, Italy.
Stem Cell Res Ther. 2019 Jan 15;10(1):29. doi: 10.1186/s13287-018-1125-5.
Cognitive deficit has been identified in one third of patients affected by Duchenne Muscular Dystrophy, primarily attributed to loss of the short Dp71 dystrophin, the major brain dystrophin isoform. In this study, we investigated for the first time the Dp71 and Dp71-associated proteins cellular localization and expression in human neurons obtained by differentiation from induced pluripotent stem cell line of a patient affected by cognitive impairment. We found structural and molecular alterations in both pluripotent stem cell and derived neurons, reduced Dp71 expression, and a Ca cytoplasmic overload in neurons coupled with increased expression of the SERCA2 pump in the dystrophic neurons. These results suggest that the reduction of Dp71 protein in the Duchenne muscular dystrophy neurons leads to alterations in SERCA2 and to elevated cytosolic Ca concentration with consequent potential disruption of the dystrophin proteins and Dp71-associated proteins.
认知缺陷已在三分之一的杜氏肌营养不良症患者中被发现，主要归因于短型 Dp71 肌营养不良蛋白的缺失，该蛋白是大脑中主要的肌营养不良蛋白同工型。在这项研究中，我们首次研究了认知障碍患者诱导多能干细胞系分化得到的人神经元中 Dp71 和 Dp71 相关蛋白的细胞定位和表达。我们发现多能干细胞和衍生神经元均存在结构和分子改变，Dp71 表达降低，神经元胞质中 Ca 超载，同时在病变神经元中 SERCA2 泵的表达增加。这些结果表明，Duchenne 肌营养不良症神经元中 Dp71 蛋白的减少导致 SERCA2 的改变以及细胞内 Ca 浓度升高，从而可能破坏肌营养不良蛋白和 Dp71 相关蛋白。
