Cell type-specific abnormalities of central nervous system in myotonic dystrophy type 1

Masayuki Nakamori; Hiroshi Shimizu; Kotaro Ogawa; Yuhei Hasuike; Takashi Nakajima; Hidetoshi Sakurai; Toshiyuki Araki; Yukinori Okada; Akiyoshi Kakita; Hideki Mochizuki

doi:10.1093/braincomms/fcac154

Cell type-specific abnormalities of central nervous system in myotonic dystrophy type 1

Brain Commun. 2022 Jun 10;4(3):fcac154. doi: 10.1093/braincomms/fcac154. eCollection 2022.

Authors

Affiliations

¹ Department of Neurology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
² Department of Pathology, Brain Research Institute, Niigata University, 1-757 Asahimachi, Chuo-ku, Niigata 951-8585, Japan.
³ Department of Neurology, National Hospital Organization Niigata National Hospital, 3-52 Akasakamachi, Kashiwazaki, Niigata 945-8585, Japan.
⁴ Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
⁵ Department of Peripheral Nervous System Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashimachi, Kodaira, Tokyo 187-8502, Japan.
⁶ Department of Statistical Genetics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.

Abstract

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.

Keywords: CAMKK2; CpG methylation; laser-capture microdissection; myotonic dystrophy; repeat expansion.