2022年7月1日 15:30～16:30 沖縄コンベンションセンター 劇場棟 第1会場
座長：高橋 良輔（京都大学大学院医学研究科）
2AL-01e
神経変性疾患における異常タンパク質の病変形成機構
Molecular mechanisms of formation and propagation of pathological proteins in neurodegenerative diseases
*長谷川 成人(1)
1. 東京都医学総合研究所 認知症プロジェクト
*Masato Hasegawa(1)
1. Tokyo Metropolitan Institute of Medical Science
Keyword: prion-like propagation, tau, alpha-synuclein, TDP-43
Intracellular accumulation of pathological proteins is the defining feature of many neurodegenerative diseases, and their spread in the brain is closely associated with disease progression. The major pathological proteins are tau, alpha-synuclein, and TDP-43, which are aggregated in brains of patients as amyloid-like filaments. In vitro and in vivo experiments have shown that these pathological proteins have prion-like properties (i.e., the ability to convert normal proteins to abnormal forms) and to propagate between cell to cell. Recent cryo-EM analyses of the pathological proteins prepared from patient brains have revealed that proteins with disease-specific folds assemble to form amyloid-like filaments. They differ among the diseases, but the same fold of protein is accumulated in a patient's brain. Therefore, structure-based classification of the diseases is proposed. Prion-like propagation is central to the pathogenesis and progression of neurodegenerative diseases. It is also important for the development of diagnostic and therapeutic strategies. | | 2022年7月3日 14:00～14:50 沖縄コンベンションセンター 会議場A1 第2会場
座長：柚崎 通介（慶応義塾大学医学部生理学）
4AL-02a
睡眠の謎に挑む～『眠気』の実体を求めて～
Deciphering the mystery of sleep: toward the molecular substrate for "sleepiness"
*柳沢 正史(1)
1. 筑波大学 国際統合睡眠医科学研究機構(WPI-IIIS）
*Masashi Yanagisawa(1)
1. International Institute for Integrative Sleep Medicine (WPI-IIIS),Univ. of Tsukuba,Tsukuba,Japan
Keyword: Sleep pressure, Orexin, Phosphoproteome, Forward genetics
Although sleep is a ubiquitous behavior in animal species with central nervous systems, the neurobiology of sleep remain mysterious. Our discovery of orexin, a hypothalamic neuropeptide involved in the maintenance of wakefulness, has helped reveal neural pathways in the regulation of sleep/wakefulness. Orexin receptor antagonists, which specifically block the endogenous waking system, have been approved as a new drug to treat insomnia. Also, since the sleep disorder narcolepsy-cataplexy is caused by orexin deficiency, orexin receptor agonists are expected to provide mechanistic therapy for narcolepsy; they will likely be also useful for treating excessive sleepiness due to other etiologies.
Despite the fact that the executive neurocircuitry and neurochemistry for sleep/wake switching has been increasingly revealed in recent years, the mechanism for homeostatic regulation of sleep, as well as the neural substrate for "sleepiness" (sleep need), remains unknown. To crack open this black box, we have initiated a large-scale forward genetic screen of sleep/wake phenotype in mice based on true somnographic (EEG/EMG) measurements. We have so far screened >10,000 heterozygous ENU-mutagenized founders and established a number of pedigrees exhibiting heritable and specific sleep/wake abnormalities. By combining linkage analysis and the next-generation whole exome sequencing, we have molecularly identified and verified the causal mutations in several of these pedigrees. Biochemical and neurophysiological analyses of these mutations are underway. Indeed, through a systematic cross-comparison of the Sleepy mutants (with a gain-of-function change in a serine/threonine kinase pathway) and sleep-deprived mice, we have found that the cumulative phosphorylation state of a specific set of mostly synaptic proteins may be the molecular substrate of sleep need. |
