パーキンソン病とその類縁疾患 Parkinson's Disease and Related Disorders
P1-1-202 パーキンソン病における血中 Neuregulin-1 SMDF の検討 Analysis of plasma NRG1 SMDF levels in Parkinson's disease ○浜結香1, 矢部一郎1, 若林孝一2, 加納崇裕1, 廣谷真1, 大庭幸治3, 岩倉百合子4, 内海潤5, 佐々木秀直1 ○Yuka Hama1, Ichiro Yabe1, Koichi Wakabayashi2, Takahiro Kano1, Makoto Hirotani1, Koji Oba3, Yuriko Iwakura4, Jun Utsumi5, Hidenao Sasaki1 北海道大学大学院・医・神経内科学1, 弘前大学大学院・医・脳神経病理学2, 北海道大学病院　高度先進医療支援センター3, 新潟大学脳研究所・分子神経生物学4, 公益財団法人がん研究会　がん研究所5 Department of Neurology, Hokkaido University Graduate School of Medicine, Japan1, Department of Neurolopathology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, Japan2, Translational Research and Clinical Trial Center, Hokkaido University Hospital, Japan3, Division of Neurobiology, Brain Research Institute, Niigata University, Japan4, Cancer Institute, Japanese Foundation for Cancer Research, Japan5 Parkinson's disease (PD) is characterised by progressive loss of dopaminergic neurons in the substantia nigra (SN). Neureguline-1 (NRG1) is a neurotrophic factor and the receptor, ErbB4, was expressed in the dopaminergic neurons of the SN. In addition, NRG1 type lll (sensory and motor neuron-derived factor (SMDF)) is one of NRG1 isoforms and mostly expressed in neuron. Based on these backgrounds, we addressed whether plasma levels of NRG1 SMDF might correlate with PD or with the clinical severity of the disorder. After we confirmed the presence of SMDF in plasma by Western blot, we then measured plasma and cerebral spinal fluid levels of NRG1 SMDF by ELISA. The plasma levels of NRG1 SMDF were correlated between the levels of cerebral spinal fluid. Next, we measured plasma NRG1 SMDF levels of normal controls, PD, multiple system atrophy (MSA) and amyotrophic lateral sclerosis (ALS). The plasma level of this protein was selectively reduced in PD when compared to controls (p< 0.025). There were no significant differences between controls and ALS or MSA patients. Plasma level of SMDF in PD did not correlate with clinical severity of UPDRS scores or Yahr stage. According to these results, reduction of plasma SMDF in PD may provide complementary information in the diagnosis and the study to the pathogenesis of PD.	P1-1-203 αシヌクレインオリゴマーによる大脳皮質錐体細胞の発火抑制機構 α-synuclein oligomer downregulates spike frequency in neocortical pyramidal neurons ○山本兼司1, 山川健太郎1,2, 澤田秀幸1,2 ○Kenji Yamamoto1, Kentaro Yamakawa1,2, Hideyuki Sawada1,2 国立病院機構宇多野病院　臨床研究部1, 国立病院機構宇多野病院　神経内科2 Clinical Research Center, Utano National Hospital1, Dept Neurol, Utano National Hospital2 Lewy body dementia (LBD), the second most frequent cause of dementia in elderly adults, refers to both Parkinson's disease dementia and dementia with Lewy bodies. LBD is pathologically characterized by the formation of Lewy bodies and neuronal death throughout the brain, including neocortex. α-synuclein, which is a major component of Lewy bodies, is proposed to play a central role in the pathogenesis of LBD, and recent evidence implicates soluble oligomers rather than insoluble fibrils as the toxic species. These data suggest the hypothesis that soluble α-synuclein oligomers could accumulate intracellularly and alter neuronal activities; however it has not been elucidated. The purpose of this study is to investigate the effect of α-synuclein on neuronal excitabilities by introducing α-synuclein protein into pyramidal neurons through whole-cell patch pipettes in mouse frontal cortex slices. The following four kinds of internal solution are applied; 1μM α-synuclein (α-SN), 10μM dopamine, 1μM α-synuclein co-incubated with dopamine at 37°C for 3 days (α-SN+DA), and vehicle solution. The application of α-SN+DA reduced spike firing by depolarizing current injection. Neither resting membrane potential, spike width, nor spike afterhyperpolarization had differences between these groups. Western blot analysis revealed that α-SN+DA included higher order oligomers compared with α-SN. These results suggest that α-synuclein oligomers lowers spike frequency, which may cause the downregulation of neocortical activities in LBD.
P1-1-204 内分泌撹乱化学物質のラットドーパミン神経系への時系列的影響 Temporal effects of endocrine-disrupting chemicals on dopaminergic neurons in the rat ○石堂正美1, 増尾好則2 ○Masami Ishido1, Yoshinori Masuo2 国立環境研究所　環境リスク1, 東邦大学、理2 NIES, Center Environ Risk Res1, Toho Univ, Funabashi, Japan2 Neurodevelopmental toxicity of endocrine-disrupting chemicals such as bisphenol A and p-nitrotoluene has been reported. We reported that hyperactivity was produced by these chemicals in the rat. The etiology of rat hyperactivity might be dopaminergic dysfunction during development Recently, the working hypothesis of the developmental origins of health and disease (DOHaD) has been developed: the etiological origin in the adult disease might be early in life during windows of developmental vulnerability. Based on this hypothesis, neonatal exposure to bisphenol A and/or p-nitrotoluene might produce the feature of Parkinson's disease, which a progressive neurodegenerative movement disorder. Therefore, the hypothesis made us examine the temporal effects of endocrine-disrupting chemicals on the rat CNS. Hyperactivity seen during 4-5 weeks of age was leveled off at 8 weeks of age, when the immunoreactivity for TH was diminished by the chemical. Then, we examined the effects of bisphenol A on dopamine neurons by microinjection and osmotic pump system of bisphenol A or p-nitrotoluene, comparing with those of 6-OHDA or rotenone, respectively, in the adult rat. In the rotation test, it was extremely few in bisphenol A-injected rats(20 μg) , compared to those in 6-OHDA-injected rats. However, immunoreactivity for TH in striatum was diminished in bisphenol A-injected rat as seen in 6OHDA(15 μg). Furthermore, we examined the effects of the chronic exposure of bisphenol A , p-nitrotoluene or rotenone, using osmotic pumps. Rotenone (3 mg/kg) significantly reduced spontaneous motor activity 49%, whereas p-nitrotoluene (3 mg/kg; 1 month) did 10%. Thus, the developing brain seems to be much susceptible to endocrine-disrupting chemicals tested, at least in behavioral traits.	P1-1-205 ニコチン受容体刺激のドーパミン神経保護に関するオートファジーの関与の検討 Neuroprotection with autophagy regulation by nicotinic receptor stimulation in dopaminergic neurons ○竹内啓喜1, 泉安彦2, 澤田秀幸3, 赤池昭紀4, 下濱俊5, 高橋良輔1 ○Hiroki Takeuchi1, Yasuhiko Izumi2, Hideyuki Sawada3, Akinori Akaike4, Shun Shimohama5, Ryosuke Takahashi1 京都大学大学院　医学研究科　臨床神経学1, 京都大学大学院薬学研究科　薬品作用解析学2, 国立病院機構宇多野病院　臨床研究部3, 名古屋大学大学院創薬科学研究科4, 札幌医科大学神経内科5 Dept Neurol, Grad Scl of Med, Kyoto Univ, Kyoto1, Dept Pharmacology, Grad Scl of Pharmaceutical Sci, Kyoto Univ, Kyoto2, Clin Reserch Center, NHO Utano Hospital, Kyoto3, Dept Basic Med Sci, Grad Scl of Pharmaceutical Sci, Nagoya Univ, Nagoya4, Dept Neurol, Sapporo Medical University, Sapporo5 We investigated neuroprotection by nicotinic receptor stimulation against protein degradation impairment. In rat cultured mesencephalic cells, nicotine protected dopaminergic(DA) neurons from tunicamycin (Tu)-induced ER stress toxicity. Furthermore, nicotine also protected DA neurons from 3-methylademine(3-MA)-induced autophagy inhibition and/or chloroquine-induced toxicity. 3-MA and chloroquine are both autophagy inhibitiors. These neuroprotecrtive effects were inhibited by α-bungarotoxin, a nicotinic α7 receptor antagonist, suggesting that nicotine rescued DA neurons against against autophagy inhibition at least through nicotinic α7 receptor stimulation. Nicotinic autophagy activation was previously reported and we discuss the relation between nicotinic autophagy activation and neuroprotection.
P1-1-206 パーキンソン病モデルラットに対する脊髄刺激による神経保護効果の検討 Neuroprotective effects of spinal cord stimulation on Parkinson's disease model of rats ○新光阿以子1, 上利崇1, 安原隆雄1, 亀田雅博1佐藤顕一郎1, 佐々木達也1, 佐々田晋1, 豊嶋敦彦1, 若森孝彰1, 三好康之1, 伊達勲1 ○Aiko Shinko1, Takashi Agari1, Takao Yasuhara1, Masahiro Kameda1, Judith Thomas Tayra1, Kenichiro Sato1, Tatsuya Sasaki1, Susumu Sasada1, Atsuhiko Toyoshima1, Takaaki Wakamori1, Yasuyuki Miyoshi1, Isao Date11 岡山大学大学院　脳神経外科1 Department of Neurological Surgery, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan1 Objective Recent studies demonstrate that the electrical stimulation therapy provide neuroprotective effects. Here we investigated neuroprotective effects of spinal cord stimulation for Parkinson's disease model of rats. Method We used female Sprague-Dawley rats (200-250g), which were classified into 4 groups, control group and stimulation groups at 2, 50 and 200Hz, respectively. All rats were underwent C1-2 laminectomy under general anesthesia with subsequent implantation of a monopolar electrode system and stimulation started immediately after implantation. Two days later, 6-hydroxydopamine (6-OHDA, 20μ) was injected into the right striatum of all rats. As behavioral evaluations, cylinder test was performed at 1 and 2 weeks after 6-OHDA lesion, and amphetamine-induced rotational test was performed at 2 weeks with consequent euthanasia for immunohistochemical investigations. Results Behaviorally, the stimulation groups showed decrease in the number of amphetamine-induced rotations, although the significant decrease (p<0.05) was found only in the stimulation group at 50Hz. Tyrosine hydroxylase (TH)-positive fibers in the striatum were significantly preserved at all the stimulation groups. TH-positive neurons in the substantia nigra pars compacta was significantly preserved in the stimulation group at 50Hz. Conclusion Spinal cord stimulation might have neuroprotective effects for Parkinson's disease model of rats.	P1-1-207 多系統萎縮症におけるオリゴデンドロサイト封入体形成の神経細胞への影響 Oligodendrocytic inclusions contribute to neuronal accumulation of α-synuclein in MSA ○鈴木康予1, 都竹佳子1, 矢澤生1 ○Yasuyo Suzuki1, Keiko Tsuzuku1, Ikuru Yazawa1 国立長寿医療研究センター　バイオリソース研究室1 Lab Research Resources, National Center for Geriatrics and Gerontology (NCGG), Aichi, Japan1 Multiple system atrophy (MSA) is a non-hereditary neurodegenerative disease in which oligodendrocytes and neurons are affected in the central nervous system. MSA is characterized by abnormal accumulation of α-synuclein inclusions in oligodendrocytes, which are diagnostic of MSA. Accumulation of α-synuclein compromises neuronal function and viability. To clearify how oligodendrocytic α-synuclein inclusions cause neuronal degeneration in MSA, we generated a transgenic mouse for an MSA model in which human wild-type α-synuclein was overexpressed selectively in oligodendrocytes. We then established primary culture cells derived from MSA model mice to investigate the mechanism of α-synuclein accumulation in neurons. Our previous studies showed novel mechanisms of neuronal α-synuclein accumulation in the MSA mouse model and identified the protein microtubule β-III tubulin, which interacts with α-synuclein to form an insoluble protein complex that progressively accumulates in neurons, thereby leading to neuronal dysfunction. Neuronal accumulation of α-synuclein was suppressed by treatment of microtubule-depolymerizing agent in primary culture cells. The binding of neuronal α-synuclein to β-III tubulin is a key process in the development of neuronal degeneration in the MSA mouse model, but it is unclear how oligodendrocytic accumulation of human α-synuclein causes neuronal accumulation of insoluble mouse α-synuclein. To address this problem, non-Tg mouse cells were treated with conditioned media derived from Tg mouse cell cultures. By treatment of the conditioned media, the expression of α-synuclein was induced, and then insoluble α-synuclein accumulation was developed in non-Tg mouse cells. Our data suggest that oligodendrocyte-drived signals are induced neuronal α-synuclein accumulation in an MSA model.
P1-1-208 ヒト本態性振戦モデルTremor (TRM/Kyo)ラットの振戦原性におけるhyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1)の役割 Hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1) is involved in tremor genesis in Tremor (TRM/Kyo) rats, a rat model of human essential tremor ○大野行弘1, 清水佐紀1, 今奥琢士1, 多田羅絢加1, 笹征史2, 芹川忠夫3, 庫本高志3 ○Yukihiro Ohno1, Saki Shimizu1, Takuji Imaoku1, Ayaka Tatara1, Masashi Sasa2, Tadao Serikawa3, Takashi Kuramoto3 大阪薬科大学　薬学部　薬品作用解析学研究室1, 渚クリニック2, 京都大学大学院　医学研究科　動物実験施設3 Lab Pharmacol, Osaka Univ Pharm Sci, Osaka1, Nagisa Clinic2, Inst Lab Anim, Grad Sch Med, Kyoto Univ, Kyoto3 TRM/Kyo rat (TRM) is a new animal model which exhibits behavioral features resembling those of human essential tremor. We previously showed that TRM has a deletion of aspartoacylase (Aspa) gene and a missense mutation in hyperpolarization-activated cyclic nucleotide-gated channel 1 (Hcn1) gene, both of which seemed to be involved in tremor genesis in TRM. Here, to clarify the role of Hcn1 in tremor generation, we studied the actions of ZD7288, a selective Hcn1 blocker, in non-tremorous TRMR/Kyo rat (TRMR) and WTC/Kyo rat (WTC), which carries only Aspa deletion (no Hcn1 mutation) and Hcn1 mutation (no Aspa deletion), respectively. ZD7288 or vehicle was intracerebroventricularly administered to TRMR or WTC and the incidence of tremor (intensity and duration) was measured for 60 sec before and 1, 2, and 4 hr after the ZD7288 injection. To explore neural excitation sites associated with ZD7288-induced tremor, expression of Fos protein was also examined throughout the brain in TRMR. Before the drug injection, intensity and duration of tremor were minimal both in TRMR and WTC. Intracerebroventricular injection of ZD7288 elicited spontaneous tremor in TRMR, which lasted over 4 hr after the injection. In contrast, ZD7288 did not induce tremor in WTC. ZD7288 evoked moderate, but non-significant, increases in Fos expression in the cerebral cortex of TRMR. In subcortical regions, however, ZD7288 significantly and region-specifically increased Fos expression in the nucleus accumbens and inferior olive while the Fos expression in the latter region was most prominent. Furthermore, electronic lesioning of the inferior olive significantly attenuated the incidence of tremor in TRM. These results suggest that both blockade of HCN1 and deletion of Aspa gene are necessary for generation of tremor in TRM. Particularly, neural excitation of the inferior olive by the dysfunction of HCN1 seems to be responsible for tremor genesis.	P1-1-209 ヒト本態性振戦モデルTremor（TRM/Kyo）ラットの振戦発現における下オリーブ核の役割 Inferior olive plays a crucial role in the pathogenesis and treatment of tremor in Tremor (TRM/Kyo) rat, a rat model of human essential tremor ○清水佐紀1, 大野行弘1, 今奥琢士1, 多田羅絢加1, 三好慧1, 安達咲希1, 木津朋也1, 笹征史2, 芹川忠夫3, 庫本高志3 ○Saki Shimizu1, Yukihiro Ohno1, Takuji Imaoku1, Ayaka Tatara1, Satoshi Miyoshi1, Saki Andatsu1, Tomoya Kizu1, Masashi Sasa2, Tadao Serikawa3, Takashi Kuramoto3 大阪薬科大学　薬学部　薬品作用解析学1, 渚クリニック2, 京都大学大学院　医学研究科　動物実験施設3 Lab Pharmacol, Osaka Univ Pharm Sci, Osaka1, Nagisa Clinic2, Inst Lab Anim, Grad Sch Med, Kyoto Univ, Kyoto3 TRM/Kyo rat (TRM) originally found in the Kyo:Wistar colony exhibits an intensive tremor at a young age (<8 wks). In this study, to clarify clinical relevance of the tremor phenotype in TRM, we examined the effects of anti-tremor agents on the incidence and magnitude of tremor in TRM and analyzed brain Fos protein expression to explore the regions involved in tremor generation. TRM (4-5 wks) was treated with anti-tremor agents as follows, propranolol and pindolol (non-selective β antagonists) and trihexyphenidyl (THP: a muscarinic acetylcholine (mACh) agonist). Incidence (duration and intensity) of tremor was measured for 1 min before and 15, 30, 45, 60 min after the drug treatment. In addition, brains from TRM or WTC/Kyo rat (WTC: non-tremorous control) were subjected to immunohistochemical staining of Fos protein and the number of Fos-imunoreactivity (Fos-IR) positive cells was counted. Before the drug treatment, TRM continuously exhibited extensive tremor in each observation period. Both total duration and intensity of tremor were significantly reduced by propranolol and pindolol in a dose-related manner. In contrast, the antiparkinsonian agent THP failed to affect the incidence of tremor in TRM, suggesting the tremor phenotype of TRM resembles the feature of human essential tremor. As compared to WTC, TRM exhibited a significant elevation of Fos expression in various regions of the cerebral cortex. However, in subcortical regions, Fos protein was region-specifically elevated in the tuberal nucleus and inferior olive. Furthermore, the treatment of TRM with propranolol region-specifically reduced Fos expression in the inferior olive. Our results suggest that TRM is useful as a novel animal model of human essential tremor and that the inferior olive plays a crucial role both in pathogenesis and treatment of tremor in TRM.
P1-1-210 α-synucleinの発現量の調節を標的とするパーキンソン病治療薬剤のスクリーニング Screening for the therapeutic drugs of Parkinson's Disease that control the α-synuclein expression ○浅野剛史1, 山門穂高1, 高橋良輔1 ○Takeshi Asano1, Hodaka Yamakado1, Ryosuke Takahashi1 京大・院医・臨床神経1 Dept Neurology, Grad Sch of Med, Kyoto Univ, Kyoto1 α-synuclein is a major component of Lewy bodies observed in the Parkinson's Disease (PD) patients. It has shown that increasing amount of α-synuclein is an important factor in pathogenic progression of familial and sporadic PD, so controlling the expression of α-synuclein may be a good target of therapy for sporadic PD. To explore the compounds that decrease the expression of α-synuclein, we generated the luciferase reporter neuronal cell lines that can be monitored the expression of α-synuclein. By using these cell lines, now we are constructing the high-throughput screening system (HTS) to identify the candidates that selectively control the expression of α-synuclein. In this symposium, we will report and discuss the ongoing process of our HTS.	P1-1-211 多価不飽和脂肪酸はドパミン神経細胞の過酸化およびリン酸化alpha-synucleinを増加させるとともにubiquitin proteasome systemの機能を低下させる DHA induced increase of modificated alpha-synuclein and dysfunction of ubiquitin proteasome system ○永井雅代1, 日坂真輔2, 大澤俊彦3, 直井信3, 丸山和佳子1 ○Masayo Shamoto-Nagai1, Shinsuke Hisaka2, Toshihiko Osawa3, Makoto Naoi3, Wakako Maruyama1 （独)長寿医療研セ・加齢健康脳科学1, 名城大・薬・生薬2, 愛知学院・心身科学・健康栄養3 Cognitive Brain Sci., Natl Ctr for Geriatri. Gerontol, Obu1, Dept. of Pharmacognosy, Fac. of Pharm., Meijo Uni, Nagoya2, Dept of Hlth. and Nutr. Fac. of Psycological & Physical Sci., Aichi Gakuin University, Nisshin3 Intra-neuronal Lewy body (LB) is the pathological hallmark of Lewy body disease, Parkinson disease (PD), Lewy body dementia (DLB), and pure autonomic failure (PAF). Alpha-Synuclein (αS) is a major component of LB and plays an important role in maintaining function of synapic vesicle and mitochondria, dopamine production and regulation of cellular redox state. Studies in familiar and sporadic PD indicated that accumulation of abnormal αS and dysfunction of proteolysis system, especially, ubiquitin ptoteasome system (UPS) were suggested to be closely associated with the pathogenic mechanism of PD. Docosahexaenoic acid (22:6n-3, DHA) is one of the most common long chain polyunsaturated fatty acids (PUFA) and is highly enriched in the neural membrane of brain and retina. DHA is a potent antioxidant but is easily oxidized by reactive oxygen species (ROS) to produce lipid peroxides. In our previous study, oligomerization and fibrillization of αS was enhanced by DHA in vitro and found to be modified by lipid peroxides derived from DHA, as proved by specific antibodies.In this work, we established human SH-SY5Y cells over-expressing αS (Syn-SH cells). After incubation with DHA, the increase of intracellular ROS production, the formation of LB-like aggregates and cell death was observed in Syn-SH cells. In the cells, proteins modified by DHA-derived lipid peroxide was detected in cytoplasm and LB-like aggregates, and in addition, the increase of phosphorylated αS (Ser129) was observed in the cytoplasm as proved by immunocytochemistry. By imunoblotting, poly-ubiquitinated proteins and phosphorylated αS (Ser129, Tyr125, Tyr133) were proved to be increased in the soluble fraction and lipid peroxide-modified αS in the insoluble fraction. These results suggest that DHA induces neuronal cell death through accumulation of various abnormal proteins such as oxidative-modified, ubiquitinated, and phosphorylated.
P1-1-212 初代培養神経細胞における α-シヌクレインの発現解析 Differential expression of α-synuclein depends on cell-types in cultured neurons ○田口勝敏1, 渡邊義久1, 辻村敦1, 田中雅樹1 ○Katsutoshi Taguchi1, Yoshihisa Watanabe1, Atsushi Tsujimura1, Masaki Tanaka1 京都府立医科大学　大学院医学研究科　基礎老化学1 Dept Basic Geriatrics, Kyoto Pref Univ of Med1 Intracellular aggregations composed of α-synuclein, for example Lewy bodies (LBs) and Lewy neurites (LNs), are well-known hallmarks of synucleinopathies including Parkinson's disease and Dementia with Lewy bodies. Although the formation of LBs and LNs is related to cell toxicity, the molecular backgrounds remain to be elucidated. Protein expression of α-synuclein is one of important factors to form the aggregates. We, therefore, observed the localization of α-synuclein and classified neurons by the expression patterns in vitro. This protein clearly localized at pre-synaptic buttons and cell bodies, whereas a certain population of the cultured neurons did not show such an intense expression pattern of α-synuclein. Although synaptotagmin is an authentic pre-synaptic marker, α-synuclein-negative synapses were also observed. These cells were identified as inhibitory neurons by using specific antibodies against parvalbumin, somatostatin, and glutamic acid decarboxylase (GAD). On the contrary, α-synuclein-positive synapses were co-localized well with vesicular glutamate transporter I, which is an excitatory synaptic marker. These results indicated that there were distinct expression patterns of α-synuclein between excitatory and inhibitory neurons. Next, we focused on the formation of intracellular aggregation of α-synuclein. Previous report revealed that preformed fibrils generated by recombinant α-synuclein can promote the formation of LB- and LN-like intracellular aggregations containing endogenous α-synuclein. After the treatment of preformed fibrils, aggregate formation was clearly confirmed and that was usually detected in GAD-negative neurons, but not in the positive-cells. Aggregate formation is possibly dependent on the expression pattern of α-synuclein of cells. These results may provide a new insight for the understanding of α-synuclein.	P1-1-213 疾患特異的iPS細胞モデルによる遺伝性パーキンソン病の研究 iPS Cell Modeling of Genetic Parkinson's Disease ○小芝泰1, 森實飛鳥2, 山門穂高1, 菊地哲宏2, 土井大輔2, 西村周泰2, 皆川栄子1, 江川斉宏2, 近藤孝之2, 井上治久2, 高橋淳2, 高橋良輔1 ○Yasushi Koshiba1, Asuka Morizane2, Hodaka Yamakado1, Tetsuhiro Kikuchi2, Daisuke Doi2, Kaneyasu Nishimura2, Eiko Minakawa1, Naohiro Egawa2, Takayuki Kondo2, Haruhisa Inoue2, Jun Takahashi2, Ryosuke Takahashi11 京都大学大学院　医学研究科　臨床神経学1, 京都大学iPS細胞研究所 臨床応用研究部門2 Dept.Neurol., Kyoto Univ. Grad. Sch. Med.1, Department of Clinical Application, Center for iPS cell Research and Application, Kyoto University, Kyoto, Japan2 Parkinson's disease(PD) is the most common neurodegenerative movement disorder, for which disease-modifying therapy has not been established. It is characterized by the progressive loss of midbrain dopaminergic(mDA) neurons in substantia nigra pars compacta(SNc) and its pathological hallmark is the presence of Lewy bodies, which contain phosphorylated alpha-synuclein. However, its pathogenic processes remain elusive. While most PD cases are sporadic, cellular and animal models of genetic PD have given us the insights into its pathogenesis. Mutations in leucine-rich repeat kinase-2(LRRK2) are the most common cause of familial PD. In addition, the genome-wide association studies(GWAS) have identified LRRK2 gene as a susceptibity locus for sporadic PD, along with alpha–synuclein(SNCA) gene. Although myriad functions have been proposed for LRRK2, their relevance to the disease remains unclear. Recently, rare variants in the glucocerebrosidase(GBA) gene are also identified as a genetic contributor to sporadic PD. A major barrier to the research on PD is inaccessibility of the diseased neurons for study. One potential solution is to derive induced pluripotent stem cells(iPSCs) from patients and differentiate them into mDA neurons affected by disease. Several recent reports have suggested iPSC-derived neural cells from genetic PD patients could recapitulate PD-related phenotypes. Here, we generate iPSC-derived mDA neurons from PD patients harboring LRRK2 and GBA mutations and explore their pathomechanisms.
P1-1-214 Withdrawn

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