TOP ＞ 公募シンポジウム

公募シンポジウム 多様なアミロイド凝集体による神経変性メカニズムの解明 7月6日（木）　14:20-16:20　Room G 1SY⑧-1 アミロイド疾患の分子標的治療を目指した核酸生物化学研究 Nucleic acid biochemical studies on molecular-targeted therapy of misfolding diseases 村上　一馬 京都大学大学院農学研究科 Kazuma Murakami Graduate School of Agriculture, Kyoto University Aggregation of amyloidogenic proteins is involved in the pathogenesis of single or multiple neurodegenerative diseases. In vitro, the aggregation of biomolecules is explained by a template-dependent mechanism. In contrast, in vivo biomolecules often coaggregate with other biomolecules (FASEB J. 2022, 36, e22493). These discrepancies are one of the reasons why drug discovery targeting amyloid are challenging. Oligomers of heterogeneous aggregates are metastable and exhibit supramolecular behavior as a toxin. We define these supramolecules as "Meta-Aggregates" and analyze the interactions with hetero-amyloid, nucleic acids, and proteins to elucidate the underlying mechanisms (e.g. Aß, αSyn, tau). In this talk, we present our initiatives to clarify how meta-aggregates are formed, and how their formation can be prevented using nucleic acid aptamer technology (JBC 2022 298, 101478). 7月6日（木）　14:20-16:20　Room G 1SY⑧-2 異種アミロイド間の相互干渉効果 Cross-interactions between different types of amyloid proteins 小野　賢二郎 金沢大学医薬保健研究域　脳神経内科学 Kenjiro Ono Dept. of Neurol., Kanazawa Univ. Neurodegenerative diseases are characterized by aggregates of proteins such as amyloid-β (Aβ), tau, and α-synuclein, the pathological forms of which appear to spread through the brain in characteristic patterns. Although each disease exhibits the accumulation of specific characteristic protein aggregates, many cases exist in which aggregation of multiple pathological proteins is exhibited. Studies in in vitro, cellular, and in vivo systems have revealed several potential types of interactions between the different pathological proteins involved in neurodegeneration, including cross-seeding of aggregates in one protein initiating misaggregation of another. In some cases, cross-inhibition effects have also been reported. To explain the mechanisms of fibril formation of amyloidogenic proteins in vitro, a nucleation-dependent polymerization model has been used. This model was originally advocated as a model for a single amyloid (Aβ), but it has also been applied with a combination of different amyloids; accordingly, it is thought that various types of seeding aggregation can occur depending on the number of amyloids involved. In this symposium, I would like to focus on amyloid proteins and their cross-seeding effects and occasionally cross-inhibition effects. 7月6日（木）　14:20-16:20　Room G 1SY⑧-3 RNA 相転移による α-Synuclein 凝集メカニズム The mechanism of α-Synuclein aggregation induced by RNA phase transition. 矢吹　悌1,2, 松尾　和哉1, 塩田　倫史1,2 1. 熊本大学発生医学研究所ゲノム神経学分野, 2. 熊本大学薬学部 Yasushi Yabuki1,2, Kazuya Matsuo1, Norifumi Shioda1,2 1. Dept. of Genomic Neuro., IMEG, Kumamoto Univ., Kumamoto, Japan, 2. Grad. Sch. of Pharma. Sci., Kumamoto Univ., Kumamoto, Japan The mechanism underling dysfunction of cellular proteostasis on α-synuclein (α-Syn) leading to pathogenesis of synucleinopathy remains unclear. Recently, we reported that the binding of an RNA secondary structure G-quadruplex (G4RNA) to a prion-like protein causes its liquid-to-solid phase transition, leading to neurodegeneration in a hereditary neurodegenerative disease (Sci Adv. 2021). Here, we introduce the possibility that G4RNA is a key pathogen on the phase transition of α-Syn. Purified α-Syn protein binds to G4 structure formed RNA specifically, but not other structures. In addition, α-Syn protein underwent liquid-liquid phase separation, and the addition of G4RNA promoted the liquid-solid phase transition under the molecular crowding. In mouse primary neurons, G4RNA aggregation was immediately observed under cellular stress conditions, thereafter co-aggregation of α-Syn with G4RNA was occurred. We also demonstrated that artificial assembly of G4RNA using an optogenetic approach initiated α-Syn aggregation, thereby elicits neuronal dysfunction in cell and in vivo. Finally, G4 ligand can ameliorate G4RNA-elicited α-Syn phase transition in vitro, in cell and in vivo. These results suggest that G4RNA assembly evoked by various cellular stress triggers to develop aggregation of α-Syn, which may be a cellular mechanism underlying onset of sporadic synucleinopathy. 7月6日（木）　14:20-16:20　Room G 1SY⑧-4 アミロイド凝集構造動態の単分子ビデオイメージング Video-imaging of structural dynamics of single amyloid aggregates 中山　隆宏 金沢大学　ナノ生命科学研究所 Takahiro Nakayama WPI-Nano Life Science Institute, Kanazawa University, Kanazawa, Japan Recent studies have revealed the correlation between amyloid fibril structure and disease types in amyloid aggregation-causing diseases. The mechanisms by which amyloid proteins form diverse fibril structures even with the same amino acid sequence has to be clarified for understanding the pathological mechanisms of amyloid diseases. However, the coexistence of various aggregate species in an aggregation process and their intrinsically disordered structures hinder the elucidation. We have used high-speed atomic force microscopy (HS-AFM) to clarify the structural dynamics of amyloid aggregation. HS-AFM can take subsecond temporal resolution movies with nanometer spatial resolution in liquid, which can simultaneously image aggregates in the observation field at the level of a single aggregate, even when diverse aggregation species coexist. Furthermore, the structure and motion of the intrinscally disordered regions can also be captured.In this presentation, we will discuss about the structural dynamics of the self-replication reaction in amyloid fibril elongation and the transient states of monomers and aggregation intermediates based on movies taken with HS-AFM. In addition, we will show that we can identify the aggregation process targeted by the drugs, showing the several examples of HS-AFM observations in the presence of the aggregation inhibitor candidate substances.