公募シンポジウム

公募シンポジウム毒か薬か？若き研究者たちが領域横断的に解き明かす蛋白質凝集体の生理活性から疾患多様性まで

7月6日（木）　16:30-18:30　Room G 1SY⑪-1 αシヌクレインが構造多型を獲得する分子機序の解明 Molecular mechanisms that alpha-synuclein acquires the fibril polymorphisms 池中　建介, Cesar Aguirre, 角田　渓太, Choong Chi-Jin, 望月　秀樹大阪大学大学院医学系研究科神経内科 Kensuke Ikenaka, Cesar Aguirre, Keita Kakuda, Choong Chi-Jin, Hideki Mochizuki Department of Neurology, Osaka University Graduate School of Medicine Although it has been hypothesized a relationship between fibril polymorphism and different pathologies, the molecular origins of polymorphism are not understood. Here, employing biophysical approaches, we demonstrate that the conformational state of the monomeric aSyn is responsible for fibril polymorphism: aSyn can exist as a compact monomer that produces rod fibrils and as extended monomers that generate twisted fibrils. Using NMR, we found that the compaction relies on a polar interaction between the initial part of the NAC region and a wide section of the C-terminus domain. The compaction can be commonly affected by changes in the chemical environment, like NaCl, the presence of Ca2+ or cellular components, like endotoxins, that alter the interaction NAC/C-terminus domain. Furthermore, we explored the factors that interact with aSyn monomer and affect the aggregation and final polymorphisms by the in vitro aggregation assay. It revealed that PIP3 not only accelerates the aggregation of αSyn, but also induces the formation of fibrils sharing conformational and biochemical characteristics similar to the fibrils amplified from the brain of PD patients.		7月6日（木）　16:30-18:30　Room G 1SY⑪-2 細胞内の蛋白質構造(分布)を原子分解能で見るー最先端・核磁気共鳴分光法(NMR)の目指すもの Toward Protein Structure (Ensemble) Analysis In a Cell - State-of-the-Art Solid-State NMR Spectroscopy 松木　陽^1,2 1. 大阪大学蛋白質研究所, 2. 大阪大学　量子情報・量子生命研究センター Yoh Matsuki^1,2 1. Institute for Protein Research, Osaka University, 2. Center for Quantum Information and Quantum Biology, Osaka University Protein fibrillation has a profound interconnection to human neurodegenerative diseases. To gain molecular mechanistic insights into the aetiology and prognosis of the diseases, atomic-resolution protein structural information especially on the initial oligomeric states is of paramount importance, not only that on the mature amyloid fibrils. Structural information of each protein in such dynamic and loose assemblies in the early stage of the protein association is notoriously inaccessible with the established methods such as X-ray crystallography and CryoEM, and thus understandings on the fibrillation triggering events is still largely elusive.Magic-angle spinning (MAS) solid-state nuclear magnetic resonance (MAS NMR) spectroscopy is uniquely able to gain such information, but strongly limited by its poor spectral sensitivity. We have been innovating the instruments for high-field dynamic nuclear polarization (DNP) technique that dramatically enhances the sensitivity of MAS NMR, which, we believe, will become a key tool for characterizing dilute protein assemblies such as those in the liquid-liquid phase-separated (LLPS) state in the physiological concentration. In the presentation, I introduce the audience the basic concepts on the DNP-enhanced MAS NMR, then touch on our preliminary data on conformational analysis of α-Syn in the LLPS droplets.

7月6日（木）　16:30-18:30　Room G 1SY⑪-3 構造イメージング技術で脳内の凝集体構造を解き明かす Structural imaging technology to elucidate the chemical structure of aggregates in the brain 長島　優浜松医科大学　光生体医工学 Yu Nagashima Dept. of Biomedical Photonics & Engineering, Hamamatsu University School of Medicine, Hamamatsu, Japan In neurodegenerative diseases, the formation of aggregates of the amyloidogenic protein in the central nervous system plays an important role. It has been clarified that the amyloidogenic protein passes through various intermediates from oligomers to fibrils in its aggregation process. Furthermore, the finally formed amyloid fibrils, which also have diverse structural polymorphisms, exert homeostatic physiological activity even in normal cells, suggesting that pathological state transitions of structural polymorphisms and disruption of physiological functions may lead to the development of diseases. Two technologies need to mature to draw an overall picture of the structural polymorphisms and state transitions of these amyloidogenic protein aggregates. The first is the maturity of molecular measurement technology. The second is the maturity of technology for selectively producing aggregate polymorphisms of amyloidogenic protein. In this presentation, I will review the molecular characteristics behind the structural polymorphisms of aggregated amyloidogenic protein. Then, I would like to outline existing molecular measurement methods and molecular imaging techniques that can be used to analyze structural polymorphisms of protein aggregates. Finally, I will propose necessary actions to deepen research on the aggregation process of amyloidogenic protein in the future.		7月6日（木）　16:30-18:30　Room G 1SY⑪-4 The discovery of new protein functions through exploration of functional amyloid 杉江　淳, 小坂　二郎, 新田　陽平新潟大学　脳研究所 Atsushi Sugie, Jiro Osaka, Yohei Nitta Brain Research Institute, Niigata University, Japan Proteins are polymer chains that express their function by folding into a unique conformation. However, proteins that fail to fold can aggregate and form amyloid fibrils. Amyloid fibrils are found in the lesions of neurodegenerative diseases, such as prion disease, Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Despite the risk of abnormal fibrosis, amyloid proteins are conserved in variety of species, suggesting its physiological significance. However, the presence of functional amyloid is largely unknown. The aim of this study is to comprehensively identify functional amyloid. For this purpose, we use a simple model organism, Drosophila, which has an advantage in high-throughput gene exploration.Amyloid proteins are known to have amino acid sequences rich in glutamine and asparagine, which are prone to forming amyloid fibrils, and are called prion domains. We used the algorithm PLAAC to search for candidate genes capable of amyloid fibril formation among 1282 genes that are strongly expressed in the nervous system, and among them, 85 genes have been chosen as candidate genes that may form amyloid fibrils. RNAi screening has been performed on these genes to further narrow down the candidate factors. We will examine whether these candidate proteins have the capacity to form amyloid fibrils as functional amyloid.