一般口演

一般口演神経変性疾患 3 Neurodegenerative Disorders 3 座長：竹内英之（横浜市立大学大学院医学研究科）

2022年7月3日　10:00～10:15　沖縄コンベンションセンター会議場B2　第5会場 4O05m2-01 PET/CT imaging reveals reactive astrocyte-mediated neuronal hypometabolism in Alzheimer’s disease patients Nam Min-Ho(1,2)、Ko Hae Young(4)、Lee Sangwon(4)、Ryu Hoon(1)、Yun Mijin(4)、Lee C. Justin(3) Min-Ho Nam(1,2), Hae Young Ko(4), Sangwon Lee(4), Hoon Ryu(1), Mijin Yun(4), C. Justin Lee(3) 1. Brain Science Institute, Korea Institute of Science and Technology, Seoul, Korea, 2. KHU-KIST Department of Convergence Science and Technology, Kyung Hee University, Seoul, Korea, 3. Center for Cogntion and Sociality, Institute for Basic Science, Daejeon, Korea, 4. Department of Nuclear Medicine, Yonsei University School of Medicine, Seoul, Korea Keyword: Alzheimer's disease, Positron Emission Tomography, 11C-acetate, Reactive astrocytes An early appearance of reactive astrocytes is a hallmark of Alzheimer’s disease (AD), providing a substrate for early diagnostic neuroimaging targets. However, there is no clinically validated neuroimaging probe to visualize the reactive astrogliosis in the human brain in vivo. Here, we report that PET/CT imaging with ¹¹C-acetate and ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) functionally visualizes the reactive astrocyte-mediated neuronal hypometabolism in the brains with neuroinflammation and AD. We demonstrate that reactive astrocytes excessively absorb acetate through elevated monocarboxylate transporter-1 (MCT1), leading to aberrant GABA synthesis and release which suppresses neuronal glucose uptake through decreased glucose transporter-3 (GLUT3) in both animal and human brains. We propose the non-invasive functional PET/CT imaging for astrocytic acetate-hypermetabolism and neuronal glucose-hypometabolism as an advanced diagnostic strategy for early stages of AD.		2022年7月3日　10:15～10:30　沖縄コンベンションセンター会議場B2　第5会場 4O05m2-02 ライソゾーム破綻によるα-シヌクレイン凝集の伝播とライソファジーによる防御応答 Lysophagy defends against propagation of α-synuclein aggregation through lysosomal rupture 角田渓太(1)、池中建介(1)、Aguirre César(1)、土居純子(1)、Choong Chi-Jing(1)、木村康義(1)、望月秀樹(1) 1. 大阪大学 Keita Kakuda(1), Kensuke Ikenaka(1), César Aguirre(1), Junko Doi(1), Chi-Jing Choong(1), Yasuyoshi Kimura(1), Hideki Mochizuki(1) 1. Osaka University Keyword: Parkinson's disease, α-synuclein, lysosome, autophagy Parkinson’s disease is the second most common neurodegenerative disease pathologically characterized by the propagation of misfolded α-synuclein (αSyn) aggregates in nervous system. Cumulative evidence has shown that aggregatedαSyn transmits from cell to cell and seeds the aggregation of soluble αSyn in recipient cell. Consistent with previous reports, we have confirmed extracellular αSyn were uptaken via endosomal-lysosomal pathway and targeted for lysosomal degradation. However, it remains unknown how the aggregates inside lysosome can interact with the native αSyn in the cytosol. To elucidate the mechanism of seeding across the lysosomal membrane, we analyzed seeding of αSyn aggregation in cell-based model, focusing on lysosomal membrane damage and selective-autophagy against damaged lysosome, known as lysophagy. αSyn aggregates induced lysosomal rupture detected by galectin-family, and aggregates-containing lysosomes were highly engulfed by autophagosome. The seeding of endogenous αSyn into aggregates occurred only at low frequency in normal condition, however, it was observed at significantly higher frequency in autophagy-deficient condition by knocking-out of FIP200 (FAK family-interacting protein of 200 kDa). Also, artificial lysosomal rupture induced by LLOMe (L-Leucyl-L-Leucine methyl ester), before or after treatment of αSyn aggregates, caused increase of seeding aggregation. Furthermore, the combination of induced lysosomal rupture and autophagy deficiency led to a much greater aggregation of cytosolic αSyn. These results suggest that exogenous αSyn aggregates interact with and seed aggregation of endogenous αSyn after escaping from endosomal-lysosomal system by rupturing lysosomal membrane. and lysophagy defends against propagation of αSyn aggregation.

2022年7月3日　10:30～10:45　沖縄コンベンションセンター会議場B2　第5会場 4O05m2-03 Nogo受容体の内因性アンタゴニストであるLOTUSはALSモデルマウスの症状を改善する Overexpression of LOTUS, the endogenous Nogo receptor antagonist, improves phenotypes of ALS model mice 池田拓也(1)、高橋慶太(1)、橋口先生俊太(1)、國井美紗子(1)、田中健一(1)、多田美紀子(1)、土井宏(1)、竹内英之(1)、竹居光太郎(2)、田中章景(1) 1. 1.横浜市立大学大学院医学研究科神経内科学・脳卒中医学、2. 2.横浜市立大学大学院生命医科学研究科生体機能医科学 Takuya Ikeda(1), Keita Takahashi(1), Shunta Hashiguchi(1), Misako Kunii(1), Kenichi Tanaka(1), Mikiko Tada(1), Hiroshi Doi(1), Hideyuki Takeuchi(1), Kohtaro Takei(2), Fumiaki Tanaka(1) 1. Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, 2. Molecular Medical Bioscience Laboratory, Yokohama City University Graduate School of Medical Life Science Keyword: ALS, LOTUS, Nogo, NgR1 [Introduction] Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive muscle weakness and atrophy due to motor neuron degeneration, which leads to eventual death in 3–5 years without mechanical ventilation. Blockade of Nogo receptor 1 (NgR1) signaling pathways has emerged as a promising therapeutic strategy for ALS because myelin-associated inhibitory molecules (MAIs), including Nogo-A, OMgp, and MAG, serve as major molecular barriers for axonal growth and regeneration via NgR1. However, clinical trials in patients with ALS have shown no significant efficacies of Nogo-A inhibitors, which does not interfere with other MAIs to bind NgR1. We previously identified Lateral Olfactory Tract Usher Substance (LOTUS) as an endogenous NgR1 antagonist which inhibits all MAIs binding to NgR1, and LOTUS may be more potent in NgR1 blockade than Nogo-A inhibitors. In this study, we investigated the efficacy of LOTUS in ALS mice. [Methods] We used G93A-mutated human superoxide dismutase 1 transgenic mice (SOD1^G93Amice) as an ALS model. We generated LOTUS-overexpressing SOD1^G93Amice and compared motor functions and survival periods with SOD1^G93A mice. Motor functions were evaluated by Rotarod test and wire hang test. We also examined expression profiles of LOTUSand MAIs, and performed pathological analysis in the lumbar spinal cords of SOD1^G93A mice using immunoblotting and immunohistochemistry. [Results] SOD1^G93A mice exhibited marked reduction of LOTUS in the lumber spinal cord compared with wild-type mice. Overexpression of LOTUS significantly improved motor functions and prolonged survival in SOD1^G93A mice. Pathological analysis showed neuroprotective effects of LOTUS on motor neurons and neuromuscular junctions. [Conclusions] Our data suggest that reduction of endogenous LOTUS in SOD1^G93Amice might enhance motor neuron degeneration by inhibiting axonal growth and regeneration. Restoration of LOTUS might be a promising therapeutic strategy for ALS.		2022年7月3日　10:45～11:00　沖縄コンベンションセンター会議場B2　第5会場 4O05m2-04 疎水領域の脆弱性により引き起こされるイヌ変性性脊髄症関連E40K変異SOD1の種特異的凝集 Vulnerability in the hydrophobic region is crucial for species-specific aggregation of canine degenerative myelopathy-linked SOD1 E40K mutation. 橋本慶(1)、渡邊征爾(1)、小峯起(1)、祖父江顕(1)、神志那弘明(2)、古川良明(3)、山中宏二(1) 1. 名古屋大学環境医学研究所病態神経科学分野、2. 岐阜大学共同獣医学科臨床放射線学、3. 慶応義塾大学化学科生命機構化学 Kei Hashimoto(1), Seiji Watanabe(1), Okiru Komine(1), Akira Sobue(1), Hiroaki Kamishina(2), Yoshiaki Furukawa(3), Koji Yamanaka(1) 1. Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University, Aichi, Japan, 2. Clinical Radiology, Joint Department of Veterinary Medicine, Gifu University, Gifu, Japan, 3. Mechanistic Chemistry for Biomolecules, Department chemistry, Keio University, Kanagawa, Japan Keyword: Canine degenerative myelopathy, Amyotrophic lateral sclerosis, Species-specific aggregation, hydrophobic region Canine degenerative myelopathy (DM), a fatal neurodegenerative disease in dogs, shares clinical and genetic features with amyotrophic lateral sclerosis (ALS), such as progressive paralysis and mutations in SOD1 gene encoding Cu/Zn superoxide dismutase (SOD1). The most widespread DM causative mutation is homozygous p.E40K in canine SOD1. Canine SOD1 with E40K mutation (cSOD1^E40K) retains enzymatic activity but forms aggregates in the spinal cords of DM-affected dogs and the cultured cells expressing cSOD1^E40K, suggesting a gain-of-toxicity mechanism. Intriguingly, E40K mutation induces aggregation of canine SOD1 but not of human SOD1, which indicates the species-specific aggregation of cSOD1^E40K. In this study, to determine the responsible mechanism of the species-specific cSOD1^E40K aggregation, we developed chimeric SOD1 cDNAs by exchanging exons between human and canine SOD1. Unexpectedly, even when we exchanged exon 2 encoding amino acids including E40 from human to canine, a single exon exchange only induced mild aggregation of chimeric SOD1. However, combinations of the two exons among exon 1, 2, and 4 promoted robust aggregation of chimeric SOD1. Moreover, when we replaced the amino acid residues encoded in exon 4 of canine SOD1 with the corresponding residues encoded in human SOD1, M117L mutation drastically ameliorated aggregation and cytotoxicity of cSOD1^E40K. In line with the cell culture data, M117L mutation increased thermal stability of recombinant cSOD1^E40K protein. Furthermore, in comparison to the crystal structure of human SOD1, we speculate that M117L filled a gap in the hydrophobic core composed of residues coded in exon 1, 2, and 4, contributing the increased protein stability. These findings indicate that the endogenous vulnerability in the hydrophobic region of canine SOD1 provokes the species-specific aggregation, consistent with the previous theories that exposure of the hydrophobic portion in human SOD1 becomes an early aggregation-prone conformer of various ALS causative human SOD1 mutants.Preventing disruption of the hydrophobic structure may be a key for developing novel therapeutic strategies for DM and SOD1-linked ALS.