TOP ＞ 臨床連携委員会・将来計画委員会・日本神経病理学会 連携シンポジウム

臨床連携委員会・将来計画委員会・日本神経病理学会 連携シンポジウム 2021/10/1　16:00～18:00　ZOOM A会場 PS2-1 若手の日本神経化学会員の皆様へのメッセージ：日本神経病理学会から Message to young members of the Japanese Society for Neurochemistry: from a senior member of the Japanese Society of Neuropathology ○柿田 明美 新潟大学脳研究所 病理学分野 ○Akiyoshi Kakita Department of Pathology, Brain Research Institute, Niigata University To provide the highest quality pathology services and scientific evidence to aid advancement in the field of neuropathology. Vision: As an academic society for specialists in pathology, we aim to deliver clinicopathological diagnostic services and perform neuropathology research with a high degree of professionalism, adopting a comprehensive and innovative approach that can strengthen the competence of society members to meet the needs of patients, academia, and society. Our approach takes full advantage of opportunities to advance both the science and practice of neuropathology through individual and collaborative research, which hopefully will produce leading practitioners and researchers. Our training course is designed to provide young practitioners with skills needed to become professional clinicopathologists, based on diagnostic expertise with both biopsied and autopsied tissue samples from patients with a range of neuropsychiatric disorders. The course and final examination confer upon candidates the title “certified neuropathologist”. One aspect of neuropathology is that it can yield human brain tissue samples as a utilizable research resource. To this end, we have launched the Japan Brain Bank Net to promote cutting-edge research to gain a better understanding the pathomechanisms underlying neuropsychiatric disorders. Collaboration proposals from the members of the Japanese Society for Neurochemistry are welcome. This communication describes recent research at my Lab, including ALSP as a “microgliopathy”, AR-JP PARK2, ALS-PNLA, snRNAseq on AD, a novel human brain tissue clearing technique, and disorders associated with noncoding repeat expansions. 2021/10/1　16:00～18:00　ZOOM A会場 PS2-2 C9orf72 リピート伸長変異に関連したFTLD/ALS の分子病態 Molecular disease mechanism of frontotemporal lobar degeneration/amyotrophic lateral　sclerosis due to C9orf72 repeat expansion mutation ○森 康治 大阪大学大学院医学系研究科 精神医学 ○Kohji Mori Department of psychiatry, Osaka University Graduate School of Medicine Frontotemporal lobar degeneration (FTLD), clinically referred to as frontotemporal dementia, is characterized with behavioral disturbance and progressive aphasia typically accompanied with frontal and/or temporal lobar atrophy. 40-50% of FTLD cases show TDP-43 pathology (FTLD-TDP). Among genetic mutations that lead to TDP-43 pathology, an aberrant intronic GGGGCC repeat expansion in C9orf72 (chromosome 9 open reading frame 72) is a leading genetic cause of familial forms of both FTLD and amyotrophic lateral sclerosis (ALS). Since the original discovery of the mutation, accumulating experimental evidence have gradually unveiled the mechanism by which the repeat causes neurodegeneration. The expanded DNA repeat is bidirectionally transcribed into sense and antisense repeat RNA. These repeat RNA transcripts sequestrate a subset of RNA binding proteins and accumulate as RNA foci. Part of the repeat RNA transcripts are even translated into dipeptide repeat protein (DPR)s in the absence of the canonical initiation codon (AUG). DPRs form disease-characterizing inclusions in the brain of C9orf72-FTLD/ALS patients. hnRNPA3 is a nucleo-cytoplasm shuttling heterogeneous nuclear ribonucleoprotein (hnRNP) that specifically binds to the repeat RNA. We revealed a reduction of hnRNPA3 leads to accumulation of repeat RNA and RNA foci as well as deposition of DPR proteins. Moreover, we recently found an RNA degradation machinery called EXOSC10/RNA exosome complex efficiently degrades C9orf72 repeat RNA. Interestingly, arginine containing DPRs impair the RNA degrading activity, resulting in further accumulation of repeat RNA. Dysregulated repeat RNA metabolism may thus underlie prominent repeat RNA and DPR depositions in C9orf72-FTLD/ALS. 2021/10/1　16:00～18:00　ZOOM A会場 PS2-3 大阪ブレインバンクの構築～病理と基礎研究の架け橋として～ Organization of the Osaka Brain Bank Network; for a bridge between Neuropathology and Basic Research ○別宮 豪一 大阪大学大学院医学系研究科 神経内科学 ○Goichi Beck Department of Neurology, Osaka University Graduate School of Medicine The causes and pathophysiological mechanisms of most neurodegenerative diseases remain unclear. It is important to study the biological causes of these diseases in human brain samples. Therefore, it is imperative to have a system in place to provide access to the human brain at the molecular and cellular level to allow researchers to study the changes that happen in the brains of patients with neurodegenerative diseases. From 2017, we started to establish the Osaka Brain Bank Network, which is a centralized resource for the collection and distribution of human brain specimens for basic brain research, in collaboration with the Department of Pathology, Osaka University, the Department of Psychiatry, Osaka University, and Osaka Toneyama Medical Center. The brain bank collects brain and spinal cord samples of patients from across the Kinki area. By end of May 2021, brain and spinal cord samples from 23 patients (Parkinson’s disease, 7; amyotrophic lateral sclerosis, 3; multiple system atrophy, 2; cerebrovascular diseases, 6; and others, 5) are stored in our department. In all patients, half of the brain and a part of the spinal cord were fixed in formaldehyde for pathological examination. The rest of the brain and spinal cord were frozen for basic research (for example, molecular study and genetic tests), so that we can provide researchers with high-quality, clinically and neuropathologically well-characterized, human brain and spinal cord tissue samples. To increase the number of autopsies, our department has introduced a lifetime consent system, the so-called “gift of hope”, and “bringing in” autopsy of patients who died in other hospitals. Finally, I would like to introduce the results of several research projects in our department using human brain tissue samples of patients with neurodegenerative diseases, including Parkinson’s disease and amyotrophic lateral sclerosis. 2021/10/1　16:00～18:00　ZOOM A会場 PS2-4 iPS 細胞技術に基づくALS や他の神経変性疾患の病態解析・創薬研究 iPSCs-based modellings of ALS and other neurodegenerative diseases ○岡野 栄之 慶應義塾大学医学部・生理学教室 ○Hideyuki Okano Department of Physiology, Keio University School of Medicine Human iPSC-based techniques offer new opportunities for disease modeling and the development of new drugs, especially for conditions such as neurological and psychiatric diseases in which access to the affected cells and pathogenic sites is limited. So far, we have established patients-specific iPSCs from more than 40 neurological and psychiatric diseases, including ALS, Alzheimer’s disease, Parkinson’s disease and so on. By developing methods to selectively induce the iPSCs into the appropriate cell type and generate 3D brain organoids, we were able to detect diseases-related pathogenic phenotypes in vitro. Today, I am going to focus on iPSCs-based investigation on ALS and other neurodegenerative diseases. We have established iPSCs-MNs models-derived from familial and sporadic ALS patients and could recapitulate ALS-related phenotypes in a dish, such as stress granule formation, abnormal protein aggregation, cell deaths of MNs and neurite retraction. Furthermore, using iPSCs-MNs derived from familial ALS patients with FUS and TDP-43 mutations, we could identify Ropinirole （ROPI) as a potential anti-ALS Drug which is further being investigated by a phase I/IIa randomized, double-blind, placebo-controlled, open-label continuation clinical trial, named ROPALS trial (UMIN000034954). In parallel with this trial, we have characterized iPSC MN-phenotypes established from more than 50 sporadic ALS (SALS)patients who participated JACALS or ROPALS trial, and found that SALS patients are very heterogenous and can be classified according to patterns of abnormal protein aggregation and neurite retractions. Collectively, iPSCs could provide innovative technologies for disease modeling and drug development.