一般口演
脊髄、運動神経および筋肉
Spinal Cord, Motoneurons and Muscle
座長：伊佐 正（京都大学大学院医学研究科） |
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| 2022年7月2日 15:00～15:15 沖縄コンベンションセンター 会議場A2 第7会場
3O07a2-01
RNA 結合タンパク質QuakingはRNA制御を介した運動ニューロンの保持に必須である
Deficiency of Quaking results in the dysregulation of RNA metabolism and motor neuron degeneration
*矢野 佳芳(1,2)、古川 貴子(1)、崎村 建司(3)、小野寺 理(3)、竹林 浩秀(1)、岡野 栄之(2)、矢野 真人(1,2)
1. 新潟大学大学院医歯学総合研究科、2. 慶應義塾大学医学部、3. 新潟大学脳研究所
*Yoshika Hayakawa-Yano(1,2), Takako Furukawa(1), Kenji Sakimura(3), Osamu Onodeara(3), Hirohide Takebayashi(1), Hideyuki Okano(2), Masato Yano(1,2)
1. Niigata Univ Grad Sch of Med and Dent Sci, Niigata, Japan, 2. Keio Univ Sch of Med, Tokyo, Japan, 3. Brain Res Inst, Niigata Univ, Niigata, Japan
Keyword: RNA-binding protein, HITS-CLIP, motor neuron, degeneration
Emerging evidence has revealed that many RNA binding proteins (RBPs) link to dysregulation of RNA metabolism in motor neuron diseases such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). However, the molecular mechanisms underlying the vulnerability of the motor neuron are yet to be elucidated. We have been focusing on the roles of cell type-specific expressing RBPs to understand how they generate cell type-specific transcriptomics and function in CNS. In this study, we searched for RBPs that generate the motor neuron-ness through the post-transcriptional network, related to MND/ALS pathology. Here we show the molecular mechanism and cellular functions of one such an RBP, Qki5 that generates motor neuron-ness. Immunohistochemical analysis and single-cell transcriptome analysis using human iPS-derived motor neuron revealed that Qki5 is specifically expressed in the motor neurons among the other types of neurons, in mouse and human spinal cord. Interestingly, RNAseq analysis of NSC-34 cells, cortical neuron and OPC revealed that Qki5 plays a crucial role to generate the motor-neuron specific transcriptome through the pre-mRNA splicing. By using mouse genetics, motor neuron-specific ablation of Qki protein causes neurodegeneration with TDP-43 proteinopathy in the young adult mouse. To further investigate Qki5 function, we used comprehensive approaches, RNAseq combined with HITS-CLIP, and discovered novel Qki5-dependent alternative splicing events including dysregulation of the ALS causative genes, which could be relevant for the maintenance of motor neuron and stress-response pathway. Finally, we will discuss the roles of an RBP Qki5 in RNA regulation to safeguard the motor neuron in various stress and a link to neurodegenerative diseases. | | 2022年7月2日 15:15～15:30 沖縄コンベンションセンター 会議場A2 第7会場
3O07a2-02
マカクザル脊髄損傷後の運動機能回復における⼤脳半球間連絡の働き
Change in contribution of the interhemispheric pathways to the recovery of dexterous hand movements after the corticospinal tract lesion in macaque monkeys
*三橋 賢大(1)、山口 玲欧奈(2)、川崎 敏生(1)、上野 里子(1)、伊佐 正(1,2)
1. 京都大学大学院医学研究科、2. 京都⼤学⾼等研究院 ヒト⽣物学⾼等研究拠点 (WPI-ASHBi)
*Masahiro Mitsuhashi(1), Reona Yamaguchi(2), Toshinari Kawasaki(1), Satoko Ueno(1), Tadashi Isa(1,2)
1. Kyoto Univ Grad Sch of Med, Kyoto, Japan, 2. Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto Univ, Kyoto, Japan
Keyword: Corticospinal tract, Interhemispheric pathway, Spinal cord injury, DREADD
Corticospinal tract (CST) lesions impair dexterous hand movements in higher primates. It is known that damaged neurons hardly regenerate in adults, but the impaired motor function recovers to some extent by rehabilitation. Therefore, the mechanism of the functional recovery is probably due to plastic change of residual neural circuits. Our group has been studying the pathways contributing to the recovery after the CST lesion at middle cervical cord (C4/5), and showed that the functional connectivity from the contralesional to the ipsilesional premotor cortices (PM) increased during the recovery (Chao et al. 2019). We hypothesized that the interhemispheric pathways are playing a role for the recovery. To prove this hypothesis, we blocked the interhemispheric pathway with chemogenetic techniques during the recovery after the CST lesion and investigated whether the recovered motor function is impaired by blocking the pathway. Macaque monkeys were trained to perform reach and grasp task. The local vector (AAV1-EF1α-DIO-hM4D(Gi)-mCherry) was injected into the left PM and the retrograde vector (AAV2retro-CAGGs-Cre) was injected into the right PM so that the unidirectional pathways from left to right PM were blocked by administrating Deschloroclozapine (DCZ). In addition, we chronically implanted the electrocorticography (ECoG) electrodes on the bilateral sensorimotor areas and longitudinally monitored the brain activities. The CST lesion at right C4/5 was made and the rehabilitation was performed. During the recovery process, we assessed the effect of blocking the interhemispheric pathway on the hand dexterity and the brain activities. Before the CST lesion, the hand dexterity was not impaired, but the functional connectivity evaluated with Granger causality from contralesional to ipsilesional PMs was decreased and movement related cortical potentials (MRCP) at ipsilesional PM was increased by administrating DCZ. During the early phase of the recovery, the hand dexterity was impaired and MRCP in the ipsilesional PM was decreased by administrating DCZ. These results suggested that the interhemispheric pathways from contralesional PM inhibited the ipsilesional PM in the intact state, while during the recovery after the CST lesion, these pathways facilitate the ipsilesional PM and contribute to the recovery of the hand dexterity. | | 2022年7月2日 15:30～15:45 沖縄コンベンションセンター 会議場A2 第7会場
3O07a2-03
脊髄損傷後の⼿指運動の機能回復に関わる 広汎脱抑制
Global disinhibition associated with recovery of hand movements after spinal cord injury
*山口 玲欧奈(1)、川崎 敏生(2,3)、Chao Zenas(2)、三橋 賢大(2,4)、上野 里子(2)、伊佐 正(1,2,5)
1. 京都大学高等研究院 ヒト生物学高等研究拠点(WPI-ASHBi) 、2. 京都⼤学⼤学院医学研究科⾼次脳科学講座神経⽣物学、3. 京都⼤学⼤学院医学研究科脳病態⽣理学講座脳神経外科、4. 京都⼤学⼤学院医学研究科脳病態⽣理学講座臨床神経学、5. 京都⼤学⼤学院医学研究科脳機能総合研究センター
*Reona Yamaguchi(1), Toshinari Kawasaki(2,3), Zenas C Chao(2), Masahiro Mitsuhashi(2,4), Satoko Ueno(2), Tadashi Isa(1,2,5)
1. Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, 2. Department of Neuroscience, Graduate School of Medicine, Kyoto University, 3. Department of Neurosurgery, Graduate School of Medicine, Kyoto University, 4. Department of Neurology, Graduate School of Medicine, Kyoto University, 5. Human Brain Research Center, Graduate School of Medicine, Kyoto University
Keyword: SPINAL CORD INJURY, MONKEY, DISINHIBITION, ECOG
Recent studies revealed that a variety of brain areas, which are not involved in the normal motor control, contribute to the control of movements during the recovery from the neuronal injury. Such a remote effect of a particular neuronal injury to the areas which are directly or indirectly connected with it is classically called “diaschisis” (von Monakow 1914), and recently the concept recaptured the attention with its possible role in the recovery process. However, the fundamental mechanism is still unclear. Here, as one of the mechanisms for diaschisis which enables postlesion reorganization of large-scaled brain networks, we propose “global disinhibition” which releases the workspace for re-learning of motor control to recruit novel areas for recovery. In this study, we chronically implanted the multi-channel electrocorticography (ECoG) electrodes in bilateral premotor cortex (PM), primary motor cortex (M1) and primary somatosensory cortex (S1), and longitudinally monitored the brain activities before and after the sub-hemisection at C4/C5 in two macaque monkeys. The monkeys started recovery of grasping from Week 3-4 post-injury. But the recovery stopped at the coarse power grip and the precision grip did not recover. The cortical electrical stimulation through each ECoG electrode (at 3 mA, 3 shocks at 20 Hz) was tested to assess the connectivity between motor cortices and motoneurons before and after the lesion. Muscle twitches started being induced in proximal muscles on the affected side from the contralesional PM/M1 after around the Week 2. The twitch responses gradually spread from the proximal to distal muscles including digits and became inducible also from the ipsilesional PM/M1. These results suggested that disinhibition occurred widely in bilateral PM/M1 during the recovery. In addition, grasping-related interhemispheric interactions from the ipsilesional to the contralesional PM/M1 in the alpha and beta bands increased. We tested the interhemispheric interaction by a conditioning paradigm. The effect of conditioning stimulus was inhibitory before the lesion as has been reported in several human studies, however, the effect was switched to facilitation during the earlier stage of recovery. These results suggested that global disinhibition occurred in bilateral PM/M1 and excitation/inhibition balance shifted to excitation in the global cortical networks, which may underlie the reorganization of large-scaled network during the recovery process. | | | |
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