Cell type-specific abnormalities of central nervous system in myotonic dystrophy type 1.
Cell type-specific abnormalities of central nervous system in myotonic dystrophy type 1.
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DOI：
10.1093/braincomms/fcac154
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发表时间：
2022
影响因子：
4.8
通讯作者：
中科院分区：
文献类型：
--
作者：
强直性肌营养不良1型是一种涉及肌肉、心脏和中枢神经系统的多系统遗传性疾病。它是由DMPK 3‘-非翻译区CTG重复序列的毒性RNA转录引起的，导致多种基因的剪接失调和多系统症状。虽然一些基因的异常剪接已被确定为某些肌肉症状的原因，但在1型强直性肌营养不良患者中普遍存在的中枢神经系统症状的发病机制仍未阐明，可能是由于对包括神经细胞和神经胶质细胞在内的不同细胞类型的研究的局限性。以往的研究发现强直性肌营养不良1型患者皮质神经元丢失、白质髓鞘丢失和轴索神经病的存在。为了阐明中枢神经系统的发病机制，我们用激光捕获显微解剖技术研究了皮质神经元、白质胶质细胞和脊髓运动神经元的细胞类型特异性异常。我们观察到不同CNS细胞系的CTG重复序列不稳定性和胞嘧啶-磷酸-鸟嘌呤(CpG)甲基化状态不同；皮质神经元比白质胶质细胞具有更不稳定和更长的重复序列，CpG甲基化水平较高；脊髓运动神经元具有更稳定的重复序列，但甲基化状态较低。我们还发现了每个中枢神经系统细胞系的剪接异常，如白质胶质细胞中的DLGAP1和脊髓运动神经元中的CAMKK2。此外，我们还证明了CAMKK2的异常剪接与强直性肌营养不良1型运动神经元中轴突的异常形态有关。我们基于激光捕获显微解剖的研究揭示了强直性肌营养不良1型中枢神经系统的细胞类型依赖的遗传、表观遗传和剪接异常，表明细胞类型特异性分析在阐明中枢神经系统的发病机制方面具有重要的潜力。强直性肌营养不良患者的中枢神经系统症状明显干扰患者的生活质量。Nakamori等人。报道患者皮质神经元、白质胶质细胞和脊髓运动神经元中特定细胞类型的遗传、表观遗传和转录特征，为强直性肌营养不良的发病机制提供新的见解。
Myotonic dystrophy type 1 is a multisystem genetic disorder involving the muscle, heart and CNS. It is caused by toxic RNA transcription from expanded CTG repeats in the 3′-untranslated region of DMPK, leading to dysregulated splicing of various genes and multisystemic symptoms. Although aberrant splicing of several genes has been identified as the cause of some muscular symptoms, the pathogenesis of CNS symptoms prevalent in patients with myotonic dystrophy type 1 remains unelucidated, possibly due to a limitation in studying a diverse mixture of different cell types, including neuronal cells and glial cells. Previous studies revealed neuronal loss in the cortex, myelin loss in the white matter and the presence of axonal neuropathy in patients with myotonic dystrophy type 1. To elucidate the CNS pathogenesis, we investigated cell type-specific abnormalities in cortical neurons, white matter glial cells and spinal motor neurons via laser-capture microdissection. We observed that the CTG repeat instability and cytosine–phosphate–guanine (CpG) methylation status varied among the CNS cell lineages; cortical neurons had more unstable and longer repeats with higher CpG methylation than white matter glial cells, and spinal motor neurons had more stable repeats with lower methylation status. We also identified splicing abnormalities in each CNS cell lineage, such as DLGAP1 in white matter glial cells and CAMKK2 in spinal motor neurons. Furthermore, we demonstrated that aberrant splicing of CAMKK2 is associated with abnormal neurite morphology in myotonic dystrophy type 1 motor neurons. Our laser-capture microdissection-based study revealed cell type-dependent genetic, epigenetic and splicing abnormalities in myotonic dystrophy type 1 CNS, indicating the significant potential of cell type-specific analysis in elucidating the CNS pathogenesis. Central nervous system symptoms in patients with myotonic dystrophy significantly interfere with the quality of life. Nakamori et al. report cell type-specific genetic, epigenetic and transcriptomic characteristics in cortical neurons, white matter glial cells and spinal motor neurons of the patients, providing new insights into the pathogenesis of myotonic dystrophy.
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影响因子：
5
作者：
Jimenez-Marin, Antonio;Diez, Ibai;Labayru, Garazi;Sistiaga, Andone;Caballero, Maria C.;Andres-Benito, Pol;Sepulcre, Jorge;Ferrer, Isidro;Lopez de Munain, Adolfo;Cortes, Jesus M.
通讯作者：
Cortes, Jesus M.
影响因子：
16.6
作者：
Freyermuth F;Rau F;Kokunai Y;Linke T;Sellier C;Nakamori M;Kino Y;Arandel L;Jollet A;Thibault C;Philipps M;Vicaire S;Jost B;Udd B;Day JW;Duboc D;Wahbi K;Matsumura T;Fujimura H;Mochizuki H;Deryckere F;Kimura T;Nukina N;Ishiura S;Lacroix V;Campan-Fournier A;Navratil V;Chautard E;Auboeuf D;Horie M;Imoto K;Lee KY;Swanson MS;de Munain AL;Inada S;Itoh H;Nakazawa K;Ashihara T;Wang E;Zimmer T;Furling D;Takahashi MP;Charlet-Berguerand N
通讯作者：
Charlet-Berguerand N
影响因子：
16.6
作者：
Du, Zhong-Wei;Chen, Hong;Liu, Huisheng;Lu, Jianfeng;Qian, Kun;Huang, CindyTzu-Ling;Zhong, Xiaofen;Fan, Frank;Zhang, Su-Chun
通讯作者：
Zhang, Su-Chun
影响因子：
23.9
作者：
Marteyn, Antoine;Maury, Yves;Martinat, Cecile
通讯作者：
Martinat, Cecile
DOI：
10.4161/rdis.25553
发表时间：
2013-01-01
期刊：
RARE DISEASES
影响因子：
--
作者：
Hernandez-Hernandez, Oscar;Sicot, Geraldine;Gomes-Pereira, Mario
通讯作者：
Gomes-Pereira, Mario