Molecular Defects in the DM Central Nervous System

  • Takashi KimuraEmail author


The central nervous manifestation of myotonic dystrophy (DM) is one of the most devastating features of this disorder, along with muscle- and heart-related symptoms. Neuropathologically, neurofibrillary degeneration accompanying hyperphosphorylated microtubule-associated tau and C(C)UG nucleotide repeat accumulation in the nucleus are observed in DM brains. CTG repeat is the longest in the cerebral cortex of DM type 1 but the shortest in the cerebellum. Non-replication processes, including transcription and repair after DNA damage, may play significant roles in repeat expansion in the central nervous system because neurons are non-mitotic. Mismatch repair protein as a trans-factor and abnormal methylation at the CTCF binding site upstream of the CTG repeat as a cis-element have been postulated as the causes of somatic instability. Because C(C)TG repeat expansion occurs in noncoding regions, the transcripts exert a toxic effect, mainly through an RNA gain-of-function mechanism. Expanded C(C)UG repeat transcripts are accumulated in the nuclei of the brain of DM patients (foci). These RNA foci sequester RNA-binding proteins MBNL1 and MBNL2, which normally regulate the splicing transition from fetal to adult isoforms, and this sequestration in the nuclei of neuronal cells leads to the retention of fetal transcripts. Although Mbnl1 knockout mice displayed DM skeletal muscle phenotypes, they only exhibit mild splicing changes in the brain. On the contrary, Mbnl2 knockout mice showed DM-CNS symptoms, indicating a major role of MBNL2 in the DM brain. However, loss of functions of both Mbnl1 and Mbnl2, demonstrated by conditional double-knockout mice, leads to dramatic splicing switch to fetal patterns, including Mapt that encodes Tau proteins. These molecular defects may contribute to synaptic dysfunction and Tau-related toxicity in the DM brain. Based on these evidences, therapeutic approaches are being tested at different levels, including clinical trials.


Myotonic dystrophy Central nervous system MBNL CELF MAPT Alternative splicing RNA-mediated disease 



I would like to thank Dr. Kuang-Yung Lee (Chang Gung Memorial Hospital, Keelung, Taiwan) for his comments regarding the manuscript.


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Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  1. 1.Division of Neurology, Department of Internal MedicineHyogo College of MedicineNishinomiyaJapan

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