公募シンポジウム
神経変性疾患を読み解く多層的な脳プロテオスタシス |
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| 7月8日（土） 8:30-10:30 Room E
3SY②-1
タンパク質ストレス応答における小胞体・ミトコンドリア接触部の新たな役割
A novel role of the mitochondria-associated membrane against proteostatic stress
渡邊 征爾, 山中 宏二
名古屋大学 環境医学研究所 病態神経科学分野
Seiji Watanabe, Koji Yamanaka
Dept Neurosci Pathobiol, RIEM, Nagoya University
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which motor neurons selectively degenerate. We have previously reported that disruption of mitochondria-associated membranes (MAM), a contacting site of the endoplasmic reticulum and mitochondria, is a pathological hallmark of ALS. However, it was still uncertain how the MAM disruption leads to motor neuron degeneration. In this study, we found that the MAM disruption compromises cellular proteostatic stress response against misfolded proteins due to the inactivation of TANK-binding kinase 1, one of the ALS causative gene products. In healthy conditions, a MAM-specific accumulation of poly-ubiquitinated proteins by E3 ubiquitin ligase glycoprotein-78 (Gp78) induced TBK1 recruitment into the MAM, which was essential for TBK1 activation. The activated TBK1 promoted the degradation of ribosomal proteins via autophagy, resulting in the formation of stress granules. Inactivation of TBK1 resulted in induced apoptosis in vitro and motor dysfunction in vivo. TBK1 inactivation was also confirmed in ALS model mice, in which the MAM is disrupted. Taken together, MAM promotes cellular prostatic stress response via TBK1 activation. Future investigation focusing on the organelle contacts, especially the MAM, will contribute to the development of a novel therapeutic approach for ALS. | | 7月8日（土） 8:30-10:30 Room E
3SY②-2
睡眠の異常を介した神経変性疾患関連タンパク質の蓄積とその臨床的意義
Accumulation of neurodegenerative disease-related proteins via sleep abnormalities and their clinical significance
皆川 栄子
国立精神・神経医療研究センター 神経研究所 モデル動物開発研究部
Eiko Minakawa
Dept. of Neurophysiol., Natl. Inst. of Neurosci., Natl. Ctr. of Neurol. and Psychiatr., Kodaira, Japan
Alzheimer’s disease (AD) and Parkinson’s disease (PD), the two most major neurodegenerative diseases, are both characterized by disrupted proteostasis. Co-morbidity of AD and PD pathology is common, especially in the elderly population. In addition, both diseases are multifactorial, where both genetic and non-genetic factors contribute to their pathogenesis. Therefore, modifiable non-genetic factors that could impact both diseases are of particular interest in developing preventive and therapeutic strategies for these diseases. Sleep abnormalities, especially sleep fragmentation resulting from frequent nocturnal arousal, are highly prevalent in patients with AD or PD. Conventionally, sleep fragmentation in the patients of AD or PD was attributed to the pathology of these diseases in the brain regions responsible for regulating sleep-wake and circadian rhythm. In contrast, in this talk, I will present our recent findings that chronic sleep fragmentation accelerates abnormal protein accumulation and the onset of disease-related symptoms in mouse models of AD and PD. These results suggest that sleep abnormalities, although often overlooked or underestimated in clinical settings, could act as a potential risk factor for the onset and progression of neurodegenerative diseases, and could serve as a novel target for preventing or delaying their disease course. | | 7月8日（土） 8:30-10:30 Room E
3SY②-3
Dynamic regulation of extracellular tau proteostasis by the glymphatic system.
山田 薫
東京大学 大学院医学系研究科 神経病理学分野
Kaoru Yamada
Department of Neuropathology, Graduate School of Medicine, The University of Tokyo
Tau spreading has significantly contributed to the progression of pathology in Alzheimer's disease (AD), which is thought to be mediated by the extracellular transfer of aggregated tau between neurons. This has raised an interesting new possibility that tau spreading might be modulated by extracellular clearance. Recently, we have discovered that extracellular tau is eliminated from brain to cerebrospinal fluid (CSF) by the glymphatic system, and then transported to deep cervical lymph nodes. Aquaporin-4 (AQP4) is a key molecule in the glymphatic clearance and facilitates its convective flows. Interestingly, the deletion of AQP4 not only impaired extracellular tau clearance but significantly worsened tau pathology and neuronal loss in tau transgenic mice, revealing its crucial role on tau-driven neurodegeneration (Ishida et al., JEM 2022). Based on these findings, we investigated whether the glymphatic system can be targeted therapeutically to prevent the progression of tau pathology using an AQP4 facilitator. We also set out to address the molecular mechanisms underlying the glymphatic dysfunction in AD and found the strong association between glymphatic dysfunction and A&beta accumulation. Along with these findings, this presentation will also review the recent knowledges of the roles of glymphatic system on AD and discuss the remaining questions and future perspectives. | | 7月8日（土） 8:30-10:30 Room E
3SY②-4
タウの生理的なプロテオスタシスの破綻が認知症発症のカギとなる
Dysregulation of lifelong proteostasis of tau is a probable cause of dementia.
宮坂 知宏
日本大学薬学部 機能形態学研究室 船橋 日本
Tomohiro Miyasaka
Laboratory of Physiology & Anatomy, Graduate School od Pharmacy, Nihon University, Funabashi, Japan
Abnormal aggregation of tau is a major pathological change leading to neurodegeneration in Alzheimer's disease and other dementias. The question of how tau lesions propagate is now focused as a target of disease modifying therapy. However, the initial trigger to tau becomes abnormal in aged brains remains obscure. Actually, although its abundance in the normal brain, tau does not immediately cause neurodegeneration. Therefore, tau is assumed to be protected from acquisition of neurotoxicity by maintaining an appropriate physiological state.Despite the numerable "abnormalities" of pathological tau were identified, it had not been well understood how physiological tau behaves in healthy brains. For example, we previously showed that tau is abundantly expressed within the perinatal period, and its expression is suppressed as brain maturation. This expression pattern is needed for axonal localization of tau and to avoid pathological aggregation in somatodendrite. In addition, most of the physiological tau is bound on microtubules, and even small amounts of free tau seems to be associated with several protein factors.Here, I would like to introduce our recent researches on physiological tau and discuss how its dysregulation leads to the acquisition of the abnormalities. | |
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