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Symposia Mysterious protein αsynuclein 1S6-1 The structure analysis for α-synuclein and Lewy bodies in the brain of Parkinson’s disease patients with synchrotron radiation Katsuya Araki1,2，Naoto Yagi3，Kensuke Ikenaka1，Hideki Hayakawa1，Kousuke Baba1，Yoshitaka Nagai4，Yuji Goto5，Hideki Mochizuki1 1Dept Neurology, Osaka Univ，2Dept Neurology,　Toyonaka Municipal Hospital，3Japan Synchrotron Radiation Research Institute，4Department of Neurotherapeutics, Osaka Univ，5Institute for Protein Research, Osaka Univ Objective: To clarify the secondary structure of α-synuclein (α-syn) and Lewy bodies (LBs) in vivo with synchrotron radiation (SR) .Background: Recently, in studies of α-syn in Parkinson's disease, the two topics are watched with interest. One is a tetramer hypothesis, the other is the propagation hypothesis. SR has the potential to provide a new knowledge for these topics.Methods: All measurements were performed at SPring-8 (Hyogo, Japan). We performed small-angle X-ray scattering (SAXS) for N-terminally acetylated α-syn (NAc α-syn) and α-syn purified from human erythrocyte (EC α-syn) and analyzed the native structure of α-syn from SAXS data. In addition, we perfomed a Fourier Transform infrared microspectroscopy (FTIRM) and X-ray diffraction for LBs in autopsy brain of Parkinson's disease patients and evaluated the secondary structure, especially the cross-β structure.Results: SAXS data showed that both NAc α-syn and EC α-syn mainly exist as a natively unfolded monomer. Our data suggested that NAc α-syn and EC α-syn are more compact than wild type α-syn (WT α-syn). FTIRM data showed that LBs have a β-sheet rich structure and the proportion of β-sheet structures was higher in the halo than in the core. On the other hand, in X-ray diffraction, we could not detect the peak signal derived from cross-β structure in the LBs. Conclusions: NAc α-syn and EC α-syn as well as WT α-syn mainly exist as a natively unfolded monomer. LBs have β-sheet rich structure, but these might not have cross-β structure like amyloid fibrils. We should carefully consider whether α-syn is a prion. 1S6-2 Pathogenic mechanism on propagation of alpha- synuclein, a pathological point of view Shigeo Murayama1，Yuko Saito2 1Dept of Neurology and Neuropathology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology，2Division of Neuropathology, Department of Pathology & Laboratory Medicine, National Center of Neurology and Psychiatry Hospital Protein propagation hypothesis was first provided by Pruisiner for prion disease and now applied to α-synuclein. Fetal grafts, which were transplanted in two patients with Parkinson disease (PD), contained Lewy bodies in more than ten years later after the operation and provided strong evidence of this hypothesis for α-synuclein. Braak proposed initial seeds of α-synuclein in tonsils and gastrointestinal tracts, propagating via glossopharyngeal and vagal nerves and reaching solitary and dorsal motor nuclei of vagus of medulla oblongata as in case of mad cow disease. Braak hypothesized rostral extension of α-synuclein from there, reaching substantia nigra to provoke PD, then limbic and neocortex to cause dementia. We proposed olfactory extension, with initial seeds in olfactory epithelia, reaching olfactory bulb, then amygdala, and extending rostrally to neocortex and caudally to brain stem. Our immunocytochemical screening of consecutive autopsy cases of our aging cohort confirmed the presence of these two types of propagation. However, there are four questions which remain to be answered. What is the correlation between oligomerization leading to cell damage and propagation of α-synuclein? 2. What form of α-synuclein is responsible for propagation? 3. What is the role of oligodendroglia, which physiologically do not express α-synuclein. 4. What is the difference between α-synuclein in PD and multiple system atrophy? 5. What is the correlation between a-synuclein and other neurodegenerative proteins like Aβ, tau and TDP43? Our brain bank is building up postmortem frozen tissue of peripheral as well as central nervous system in order to support any research theme to answer these questions. 1S6-3 Roles of neuronal exosomes in the progression of alpha-synuclein Rikinari Hanayama1，Hironori Kawahara1，Tatsusada Okuno2，Hideki Mochizuki2 1Dept of Immunology, Kanazawa University，2Dept of Neurology, Osaka University Multiple system atrophy (MSA) is a progressive neurodegenerative disease, which causes motor and autonomic nervous symptoms. Pathologically, alpha-synuclein (α-syn) aggregates and forms inclusion bodies, which accumulate in oligodendroglia in a wide area of the central nervous system. α-syn is also a constituent of Lewy bodies in Parkinson's disease and is considered to be the cause of neurodegeneration. However, as α-syn is mainly expressed by neurons but not by oligodendroglia, it has been a mystery how α-syn accumulates in oligodendroglia of MSA patients. We recently found that α-syn mRNA (SNCA mRNA) is recruited inside neuronal exosomes in a calcium stimulation-dependent manner and is transferred to oligodendroglia via the exosomes for the translation of α-syn protein. Furthermore, we identified a molecule that mediates the encapsulation of SNCA mRNA in the exosomes and also a molecule that promotes degradation of α-syn in oligodendroglia. We are currently investigating the relationship between these mechanisms and pathogenesis of MSA. 1S6-4 α-synucleinopathy as Oligomeropathy Kenjiro Ono Dept of Neurol. Sch of Med, Showa Univ Lewy bodies are the main histopathological features of α-synucleinopathies such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB), and are comprised of amyloid-like fibrils composed of a small protein (~14 kDa) named α-synuclein (αS). Although αS aggregates from a monomer to assemblies such as oligomer, protofibril and mature fibril, the early intermediate aggregate, that is, oligomer has been considered to be most toxic species in recent reports (oligomer hypothesis). While it was reported that αS concentration in cerebrospinal fluid (CSF) was decreased significantly in the patients with PD and DLB, there were reports that αS oligomer concentration was elevated in CSF of PD patients. Thus, the inhibition of the oligomerization of αS has been suggested as a possible therapeutic target for the fundamental treatment of α-synucleinopathies. I summarize here recent research efforts targeting αS oligomers.