臨床神経学
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49 巻 , 11 号
選択された号の論文の86件中1~50を表示しています
第50回日本神経学会総会(2009年)
会長講演
  • 糸山 泰人
    49 巻 (2009) 11 号 p. 699-707
    公開日: 2009/12/28
    ジャーナル フリー
    「multiplicity in time and space in CNS」を診断基準の骨子とする多発性硬化症(multiple sclerosis,MS)の診断には多様な病態と疾患がふくまれる可能性がある.MSの認識が遅れた日本では,視神経や脊髄に病変の主座をおく再発性の炎症性疾患はMSと考えられ,視神経脊髄型MS(OSMS)としてアジアのMSの特徴とされてきた.一方,欧米では類似の疾患を視神経脊髄炎(neuromyelitis optica,NMO)とよんできたが,両疾患には多くの臨床的および検査学的所見の共通性があることや,最近発見されたNMO-IgGが共通に存在することを考えると両者は同一疾患と考えられる.このNMO-IgGはNMO/OSMSにのみにみられMSにはみとめられない血清抗体で,その標的抗原はwater channelのaquaporin4(AQP4)でありアストロサイトに局在している.このNMO-IgGに加えてNMO/OSMSが示す臨床的特徴,すなわち視神経と脊髄という病変部位の選択性,極端な女性優位性,3椎体以上の長さのMRI脊髄病巣,髄液オリゴクローナルバンドが陰性である点などを考えてみると,NMO/OSMSとMSはきわだった差異を示していることに気付かされる.さらに,免疫組織化学的にはNMO/OSMSの脊髄病変ではAQP4とアストロサイトのマーカーであるGFAPの染色性が欠落しているが,MBP陽性の髄鞘は病変で比較的保たれていることが明らかとなった.この所見はMBPのみが欠損するprimarily demyelinating diseaseであるMSの病変特徴とは根本的に異なるものであり,NMO/OSMSはMSと病態を異にする疾患と考えられる.加えて,急性期のNMO患者の髄液では著明なGFAPの増加があり,NMOはastrocyteがprimaryに傷害される新たな概念の疾患と考えられる.現在,AQP4抗体が関与するNMOの病態機序が培養系や動物モデルで明らかにされつつある.今後はNMOへの新たな治療法の開発が求められる.
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招待講演1
招待講演2
  • 平野 朝雄
    49 巻 (2009) 11 号 p. 719-723
    公開日: 2009/12/28
    ジャーナル フリー
    Neuronとgliaは,よく発達した突起をもち,細胞間を連絡する特別な構造があります.Neuronは円柱状の突起を伸ばしてsynapsesを形成し,それに対し,gliaの突起の末端は布状の大きな広がりを形成します.Oligodendrogliaの突起はaxonの周りにシャベル状の髄鞘板を形成するのに対し,astrocyteの突起は中枢神経系を包み,外部組織から隔離し,中枢神経系実質内の血管周囲を取りかこみます.更に,neuronのsomaおよびdendritesを包み,無数のsynapsesと接しています.こうした解剖学的所見は,電子顕微鏡で詳細に観察することができます.私はこの半世紀にわたり神経病理学に携わってきました.そして,そのあいだに,neuronとgliaの突起にみられるいろいろな思いがけぬ興味ある所見に驚かされてきました.その中でとくに強く印象を受けたエピソードを記載します.
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50周年記念講演
  • 高橋 昭
    49 巻 (2009) 11 号 p. 724-730
    公開日: 2009/12/28
    ジャーナル フリー
    日本神経学会は1960年4月15,16両日福岡市において勝木司馬之助九州大学内科学教授を会長として第1回「日本臨床神経学会」総会を開催,1963年第4回総会(大阪)において「日本神経学会」と改称,2009年仙台市において第50回総会を迎えた.学会の機関誌『臨床神経学』は1960年10月に創刊号を発行,学会名は変更になったが,会誌名の変更はなく今日に至る.今日の「日本神経学会」の誕生には,多くの紆余曲折があり多難な道程であった.1902年には「日本神經學會」が設立されたが,精神医学関係者の会員が増加し,1935年に「日本精神神經學會」と改称された.この学会では勝沼精藏が神経学関係者として久しく孤城を守っていたが,1946年から冲中重雄らが加わり,1954年に同会の「神経学部門」が独立した.1956年には「内科神経同好会」が結成,1959年11月9日第5回内科神経同好会(東京)において「日本臨床神経学会」設立が承認され,1960年4月に「日本臨床神経学会」が設立された.
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50周年記念シンポジウム
日本神経学会2008年度学会賞受賞者招待講演
  • 小野寺 理
    49 巻 (2009) 11 号 p. 750-752
    公開日: 2009/12/28
    ジャーナル フリー
    神経細胞の機能を維持するために,神経細胞の内部環境を維持する品質管理機構が重要である.とくに蛋白質と核酸の品質管理機構と神経変性疾患との関係が注目されている.代表的な優性遺伝性脊髄小脳変性症であるポリグルタミン病では,蛋白質の品質管理機構の異常が推察されている.一方,劣性遺伝性脊髄小脳変性症では核酸品質管理機構の異常が推察されている.神経細胞のDNAは活性酸素などにより常に障害をうけ損傷している.損傷部の3'末断端はリン酸基,ホスホグリコール酸基または不飽和アルデヒド基となっており,修復のためには,水酸基に置換(エンド・プロセッシング)される必要がある.われわれは劣性遺伝性脊髄小脳失調症の原因遺伝子アプラタキシンの生理機能を検討し,この蛋白質がin vitroにおいて3'末断端のリン酸基およびホスホグリコール酸基を除去し水酸基とする活性を持ち,これにより損傷部のエンド・プロセッシングに関与していることを示した.このことから,本症の病態機序としてDNA損傷の蓄積の関与を示唆し,脊髄小脳変性症での核酸品質管理機構の重要性を示した.
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日本神経学会2008年度楢林賞受賞者招待講演
特別企画1
特別企画2
教育講演1
  • 辻 貞俊
    49 巻 (2009) 11 号 p. 769-773
    公開日: 2009/12/28
    ジャーナル フリー
    The task force of the international league against epilepsy (ILAE) proposed the "Diagnostic scheme for people with epileptic seizures and epilepsy" in 2001. The 2001 diagnostic scheme was updated in 2006. The ILAE Core Group recommended the new classification to replace the previous one (ILAE, 1981, 1989). However, the new classification is too complex to use for clinicians except expert epileptologists.
    About 10 new antiepileptic drugs are launched recently. Among them, gabapentine, topiramate, and lamotrigine have been approved in Japan as adjunctive therapy for medically intractable seizures. The advantage of the new antiepileptic drugs includes newer mechanism of action, broad spectrum of anti-seizure effects, fewer side effects, and lesser drug interactions. The rational polytherapy is necessary for refractory epilepsy. The majority of elderly patients with new onset epilepsy become seizure free on antiepileptic monotherapy, often with modest dose.
    We are now in the new era of epilepsy treatment.
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教育講演2
  • 飯塚 高浩
    49 巻 (2009) 11 号 p. 774-778
    公開日: 2009/12/28
    ジャーナル フリー
    Recently a new category of treatment-responsive encephalitis has been proposed associated with antibodies against neuronal cell membrane antigens, including VGKC, NMDA receptor (NMDAR) and AMPA receptor. Anti-NMDAR encephalitis is caused by the antibodies, which bind to extracellular conformal epitope in the NR1/NR2 heteromers of the NMDAR. The antibodies are usually detected in CSF/serum of young women with ovarian teratoma (OT), who typically developed schizophrenia-like psychiatric symptoms. Most patients developed seizures, followed by unresponsive/catatonic state, central hypoventilation, and bizarre orofacial-limb dyskinesias.
    Based on symptomatology and current NMDAR hypofunction hypothesis in schizophrenia, we speculated that the antibodies might cause inhibition of NMDAR in presynaptic GABAergic interneurons, causing a reduction of release of GABA. This results in disinhibition of postsynaptic glutamatergic transmission, excessive release of glutamate in the prefrontal/subcortical structures, and glutamate/dopamine dysregulation. Recent studies demonstrated that the antibodies cause reversible reduction in the numbers of cell-surface NMDAR and NMDAR clusters in postsynaptic dendrites, suggesting antibodies-mediated decreased function of NMDAR. Early tumor resection with immunotherapy is recommended in OT-positive cases but not in OT-negative cases. However, exploratory laparotomy may increase the chance to identify microscopic teratoma and improve the outcome if patients who were refractory to immunotherapy had anti-NMDAR antibodies and ovarian cyst.
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教育講演3
  • 井上 和秀
    49 巻 (2009) 11 号 p. 779-782
    公開日: 2009/12/28
    ジャーナル フリー
    痛みを伝える末梢神経の損傷や機能異常は神経障害性疼痛という耐えがたい慢性疼痛をひきおこす.しかし,その発症メカニズムが不明のために有効な治療法がなく,モルヒネなどの鎮痛薬も奏功しがたく,全世界で2,200万人以上の患者が苦しんでいるとされている.われわれは,末梢神経損傷後に脊髄で活性化したミクログリア細胞にイオンチャネル型P2プリン受容体サブタイプP2X4受容体が過剰発現し,その受容体刺激が神経障害性疼痛に重要であること,更に,P2X4受容体の活性化によりミクログリアから脳由来神経栄養因子(BDNF)が放出され,それが痛覚二次ニューロンのCl-イオンくみ出しポンプの発現低下をひきおこし,それゆえ,触刺激により放出されたGABAの二次ニューロンに対する作用が抑制性から興奮性へと変化し,このようにして,触刺激が疼痛をひきおこすことを示した.その後更に,P2X4受容体過剰発現メカニズムや,ミクログリアの活性化がインターフェロンガンマによりひきおこされることをみいだした.また,活性化ミクログリア細胞にはP2Y12受容体が発現し,独特のメカニズムで神経障害性疼痛に関与する.これらの事実は,神経障害性疼痛発症におけるP2プリン受容体-ミクログリア-ニューロン連関の重要性を示唆している.
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教育講演4
  • 長谷川 成人, 野中 隆, 山下 万貴子, 亀谷 富由樹, 新井 哲明, 吉田 眞理, 橋詰 良夫, 土谷 邦秋, 秋山 治彦
    49 巻 (2009) 11 号 p. 783-785
    公開日: 2009/12/28
    ジャーナル フリー
    The TDP-43 proteinopathies: Toward understanding of the molecular pathogenesis. TAR DNA binding protein of 43kDa(TDP-43), a heterogeneous nuclear ribonucleoprotein was identified as a major component of ubiquitin-positive inclusions in FTLD and ALS, and the concept of TDP-43 proteinopathies was proposed. Immunoblot and immunohistochemical analyses using multiple anti-phosphorylated TDP-43 antibodies revealed that hyperphosphorylated 18-26kDa C-terminal fragments in addition to the full-length TDP-43 are major constituents of inclusions in FTLD-U and ALS. Recent discovery of mutations in the TDP-43 gene in familial and sporadic ALS, indicating that abnormality of TDP-43 protein cause neurodegeneration. It also strongly suggests that aggregation of TDP-43 or the process is responsible for neurodegeneration in FTLD-U and ALS. To investigate the molecular mechanisms of aggregation of TDP-43, we have established two cellular models for intracellular aggregates of TDP-43 similar to those in brains of TDP-43 proteinopathies patients. The first consists of SH-SY5Y cells expressing mutant TDP-43 that lacks both the nuclear localization signal (NLS) and residues 187-192 (ΔNLS & 187-192). The second model consists of SH-SY5Y cells expressing an aggregation-prone TDP-43 C-terminal fragment as a green fluorescent protein (GFP)-fusion. In these cells, round structures positive for both anti-pS409/410 and anti-Ub are observed. These results suggest that intracellular localization of TDP-43, truncation of TDP-43 and proteasomal dysfunction of cells may be involved in the pathological process of TDP-43 proteinopathies. We also found that two small compounds that have been reported to be beneficial in phase II clinical trials of Alzheimer's disease, inhibited the formation of TDP-43 aggregates in these two cellular models, suggesting that these compounds may be effective for the treatment of ALS and FTLD-U.
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教育講演5
  • 安井 正人
    49 巻 (2009) 11 号 p. 786-788
    公開日: 2009/12/28
    ジャーナル フリー
    体内水分バランスは,生体の恒常性維持機能のもっとも重要な調節機構である.水分バランスの不均衡は,様々な病態にともなってみとめられ,その補正が治療上有効となることが多い.水チャネル,アクアポリンの発見は,体内水分バランスや分泌・吸収に対するわれわれの理解を分子レベルまで深めることとなった.腎臓における尿の濃縮・希釈はもちろんのこと,涙液・唾液の分泌にも重要な働きをしている.アクアポリンの結晶構造が解明されたことで,水分子がいかにしてアクアポリンのポアを選択的に通過するか,分子動力学シミュレーションを駆使して再現することも可能となった.アクアポリンの調節機構に対する理解も進みつつあり,アクアポリンを標的とする創薬への期待が高まっている.脳においても水バランスの重要性は例外ではない.アクアポリンの分布から考えて,神経細胞ではなくグリア細胞がその役割を担っていると考えられている.グリア細胞に発現しているアクアポリン-4(AQP4)は,脳浮腫の病態生理に関与している事が明らかになったのみならず,最近ではNMOの患者に特異的にみとめられるNMO-IgGの抗原としてAQP4が同定されるなど,AQP4は臨床的にも大変注目を集めている.AQP4の立体構造も解明され,分子標的創薬の面からも期待が高まっている.
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教育講演6
  • 高守 正治
    49 巻 (2009) 11 号 p. 789-793
    公開日: 2009/12/28
    ジャーナル フリー
    Autoantibodies impair acetylcholine receptor (AChR) in myasthenia gravis (MG) and P/Q-type voltage-gated calcium channel (VGCC) in Lambert-Eaton myasthenic syndrome (LEMS). (1) Some of MG and LEMS patients are "seronegative" for respective antibodies or modified by antibodies that recognize other proteins than AChR and VGCC such as MuSK, AChR allosteric site, membrane Na+ channel and ryanodine receptor-1 (RyR1) in MG, and synaptotagmin-1 in LEMS. (2) Autoimmune responses affect the proteins participating in the mechanisms to compensate for synaptic disorders on the basis of presynaptic Ca2+ homeostasis provided by VGCC and non-VGCC (receptor-operated TRPCs); they act as enhancers of Ca2+-mediated ACh release via phospholipase C signaling pathways including M1-type presynaptic muscarinic AChR, neurotrophin receptor (TrkB), and fast-mode of synaptic vesicle recycling. (3) The pathophysiology contributive to contractile fatigue in MG includes RyR1 and also TRPC3. The TRPC3 also forms a complex with STIM1 and Orai1 to make up for Ca2+ after sarcoplasmic Ca2+ release. The prevalent detection of anti-TRPC3 antibodies in MG with thymoma could affect muscle contractile machineries in addition to anti-RyR1-induced affection. (4) When one faces "seronegative" MG, one should be cautious to conformation-specific antibodies and also congenital myasthenic syndromes.
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教育講演7
  • 鈴木 匡子
    49 巻 (2009) 11 号 p. 794-796
    公開日: 2009/12/28
    ジャーナル フリー
    Conscious awareness is the state in which external and internal stimuli are perceived and can be intentionally acted on. Although various investigations have provided new insights into the neural mechanisms of conscious awareness, its whole network in human remains to be solved. Anosognosia for visual dysfunction and unconscious processing of visual stimuli are good examples of dissociation between cognitive processes and conscious awareness.
    Anton syndrome, anosognosia for blind or deaf, could be observed in blindness caused by cerebral as well as ophthalmological diseases, when general cognitive function or attention is impaired. Unawareness of hemianopia is not an exception but a common phenomenon, which seems to be related to a completion phenomenon and macular sparing. Patients with visual agnosia are not consciously aware of the nature of their visual dysfunction but have a vague feeling of visual impairment.
    Blindsight, unconscious visual processing in the blind field, might be partly related to the dorso-dorsal visual stream that takes roles in the control of actions "on line" without awareness of spatial perception. In patients with unilateral spatial neglect, unconscious processing of visual stimuli on the neglected space was also observed.
    Better understanding of neural mechanisms of conscious awareness would provide insights into various neurological disorders and therapeutic approaches.
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シンポジウム1:脳梗塞UP TO DATE
シンポジウム2:ALS治療法開発の将来
  • 三本 博, 祖父江 元
    49 巻 (2009) 11 号 p. 810
    公開日: 2009/12/28
    ジャーナル フリー
  • 田中 章景, 和座 雅浩, 山本 正彦, 祖父江 元
    49 巻 (2009) 11 号 p. 811-813
    公開日: 2009/12/28
    ジャーナル フリー
    The mechanisms underlying motor neuron degeneration in amyotrophic lateral sclerosis (ALS) remain poorly understood even now 140 years after the first description of the disease in 1869 by Jean-Martin Charcot. Exploration of pathogenesis of ALS has long been dependent on transgenic animal models with mutations in the copper/zinc superoxide dismutase 1 (SOD1) gene. However, the lack of therapeutic concordance between these animal models and human sporadic ALS patients is troubling. The reasons include that there might exist the differences of pathogenesis between sporadic and familial ALS and/or the disease models for sporadic ALS have not bee established. We have been working on screening motor neuron-specific genes critical for pathogenesis of sporadic ALS using cDNA microarray and laser capture microdissection techniques. Many of the resultant genes are of intense interest and may provide a powerful tool for determining the molecular mechanisms of sporadic ALS. In particular, dynactin-1, a major component of dynein/dynactin complex and several cell cycle-related genes are the targets of our research. Development and analysis of new disease models for sporadic ALS based on these genes will open an avenue for novel therapeutics.
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  • 青木 正志, 割田 仁, 鈴木 直輝, 糸山 泰人
    49 巻 (2009) 11 号 p. 814-817
    公開日: 2009/12/28
    ジャーナル フリー
    Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disorder characterized by the death of upper and lower motor neurons. Approximately 20% of familial ALS cases are caused by mutations in the superoxide dismutase 1 (SOD1) gene. Mutations in the fused in sarcoma/translated in liposarcoma (FUS/TLS) gene have been recently discovered to be associated with familial ALS. We found FUS/TLS mutations in familial ALS cases in Japan. Even in Asian races, ALS with FUS/TLS mutations may have common characteristics of early onset, rapid progress, high penerence trait.
    We developed rats that express a human SOD1 transgene with two different ALS-associated mutations (G93A and H46R) develop striking motor neuron degeneration and paralysis. The larger size of this rat model as compared with the ALS mice will facilitate studies involving manipulations of spinal fluid (implantation of intrathecal catheters for chronic therapeutic studies; CSF sampling) and spinal cord (e.g., direct administration of viral- and cell-mediated therapies).
    Hepatocyte growth factor (HGF) is one of the most potent survival-promoting factors for motor neurons. To examine its both protective effect on motor neurons and therapeutic potential, we administered human recombinant HGF (hrHGF) by continuous intrathecal delivery to G93A transgenic rats at onset of paralysis for 4 weeks. Intrathecal administration of hrHGF attenuates motor neuron degeneration and prolonged the duration of the disease by 63%. Our results indicated the therapeutic efficacy of continuous intrathecal administration of hrHGF in ALS rats. In addition, HGF is capable of reducing astrocytosis and microglial accumulation, and thus supports the attention of a glial-dependent mechanism of ALS progression. These results should prompt further clinical trials in ALS using continuous intrathecal administration of hrHGF.
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  • 漆谷 真
    49 巻 (2009) 11 号 p. 818-820
    公開日: 2009/12/28
    ジャーナル フリー
    Emerging evidence suggests that misfolded proteins in the various neurodegenerative diseases can be targets for immunotherapy including vaccination antibody therapy. To date, vaccination strategies have been shown to be effective in Alzheimer's disease, Parkinson's disease, Huntington's disease and Prion disease. Interestingly, the subcellular localization of the target proteins varies, including cytosol, synaptosomes and extracellular spaces. We have documented that mutant SOD1 is secreted together with a neurosecretory protein chromogranin, and that vaccination against the SOD1 mutant is beneficial in delaying the onset and prolonging the lifespan. However, the mechanism of vaccination on the mutant SOD1 mice remains unclear. Moreover, vaccination induces diverse inflammatory reactions, which are reported to modify both the onset and the progression of ALS. Therefore, it is important to clarify the role of innate or acquired immunity in the pathogenesis of ALS to avoid the adverse reactions of the vaccination, and rather to apply it for amelioration. Passive immunization is also promising since only aberrant proteins can be targeted using a specific monoclonal antibody. The development of the current immunization techniques is very important for the future application, since key molecules for the sporadic ALS have emerged and are intensively investigated such as TDP-43.
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  • 横田 隆徳
    49 巻 (2009) 11 号 p. 821-823
    公開日: 2009/12/28
    ジャーナル フリー
    家族性ALSにおいて変異遺伝子自体をshort interfering RNA(siRNA)で治療するといった究極の遺伝子治療を目ざした基礎研究が進行し,SOD1変異による家族性ALSモデルマウスをもちいた治療実験では良好な結果がえられている.神経細胞へのデリバリーの方法にも新しい進歩は報告されている.off-target効果,short hairpin RNA(shRNA)毒性など,まだまだ解決すべき問題点も多いが,siRNAの高い抑制効果からALSへの応用が急速に進展していくことはまちがいないものと思われる.
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シンポジウム3:中枢神経系の再生・次なる半世紀
  • 岡野 栄之, 水澤 英洋
    49 巻 (2009) 11 号 p. 824
    公開日: 2009/12/28
    ジャーナル フリー
  • 岡野 栄之
    49 巻 (2009) 11 号 p. 825-826
    公開日: 2009/12/28
    ジャーナル フリー
    Induced pluripotent stem (iPS) cells are pluripotent stem cells directly reprogrammed from cultured mouse fibroblast by introducing Oct3/4, Sox2, c-Myc, and Klf4. Cells obtained using this technology, which allows the ethical issues and immunological rejection associated with embryonic stem (ES) cells to be avoided, might be a clinically useful source for cell replacement therapies. We found that secondary neurospheres (SNSs) generated from various mouse iPS cell showed their neural differentiation capacity and teratoma formation after transplantation into the brain of immunodeficient NOD/SCID mice. We found that origin (source of somatic cells) of the iPS cells are the crucial determinant for the potential tumorigenicity of iPS-derived neural stem/progenitor cells and that their tumorigenicity results from the persistent presence of undifferentiated cells within the SNSs. Surprisingly, SNSs derived from c-Myc minus iPS cells generated without drug selection showed robust tumorigenesis, in spite of their potential to contribute adult chimeric mice without tumor formation. Furthermore, we examined whether the transplantation of non-tumorigenic Nanog-iPS-derived SNSs into mouse spinal cord injury (SCI) model could promote locomotor function recovery. As a result, we found that properly pre-evaluated iPS clone-derived neural stem/progenitor cells may be a promising cell source for future transplantation therapy of SCI.
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  • 木山 博資
    49 巻 (2009) 11 号 p. 827-829
    公開日: 2009/12/28
    ジャーナル フリー
    The central nervous system (CNS) injury causes severe loss of functions, and the development of therapies to recover the functions can be an important target. The present study highlighted the preservation-oriented therapy by transferring genes to the injured neurons. To identify therapeutic targets for the preservative therapies of injured CNS, we focused on clarifying the mechanism underlying the degeneration and regeneration of neurons after injuries using nerve injury models of animals. We have identified several genes, some of which were the survive-promoting and others were death-promoting molecules. In addition another subset of genes were assumed to be associated with promoting nerve regeneration. The single expression of variety of molecules by a viral vector was proved to have the potential to rescue and recover, and this was also confirmed in CNS injury model. We assumed that the most important issue was the balance of levels between the pro-survive and pro-death molecules, which expressed in response to nerve injury. Those suggest that variety of molecules could be a therapeutic target for neurodegenerative disease as well as the neuron protection after traumatic injury. Combining both the transplantation-oriented and the preservation-oriented strategies would give us more potent therapeutic possibilities.
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  • 澤本 和延
    49 巻 (2009) 11 号 p. 830-833
    公開日: 2009/12/28
    ジャーナル フリー
    脳を構成するニューロンの大部分は胎生期あるいは生後の初期に神経幹細胞から生まれる.しかし,近年の研究によって成人の脳にも幹細胞が存在し,ニューロンが継続的に産生されていることが明らかになった.成熟した脳におけるニューロンの産生(adult neurogenesis)は,霊長類をふくむ様々な動物の側脳室の外側壁に存在する脳室下帯(subventricular zone:SVZ)で観察されている.脳室下帯で生まれるニューロンは長距離を移動し,実際に機能する場所へ到達した後で成熟する.本講演では,われわれが動物実験で明らかにした正常時・病態時におけるニューロンの産生・移動・成熟のメカニズムと,それを活かした虚血性脳疾患の再生医療の可能性について述べる.
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  • 高橋 淳
    49 巻 (2009) 11 号 p. 834-836
    公開日: 2009/12/28
    ジャーナル フリー
    Embryonic stem (ES) cells are expected as promising donor cells for cell transplantation therapy. For example, mouse or monkey ES cell-derived dopamine (DA) neurons can survive in the brain and relieve Parkinson's disease (PD) symptoms in rat or monkey models. In 2001 and 2003, the results of a double-blind trial of the transplantation of human embryonic DA neurons into patients with PD were reported. These results teach us two things. First, cell transplantation has been clinically proven to be effective as a treatment for PD, although the effects are still far from optimal. Second, several problems remain to be solved, including patient selection, optimal donor cell volume, targeting of injection, immunosuppression, and control of dyskinesia.
    DA neurons have also been generated from several human ES cell lines. Furthermore, functional recovery of rat PD models after transplantation was observed. One of the major problems in ES cell transplantation is tumor formation, which is caused by a small fraction of undifferentiated ES cells in the graft. So, it is essential for undifferentiated ES cells to be eliminated from the graft for clinical application. These efforts will lead to clinical application of ES cell transplantation to the patients with PD.
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シンポジウム4:アルツハイマー病の診断と治療開発
シンポジウム5:難治性筋疾患の病態機序―CK発見から50年―治療の時代へ
  • 杉田 秀夫, 清水 輝夫
    49 巻 (2009) 11 号 p. 851
    公開日: 2009/12/28
    ジャーナル フリー
  • 西野 一三, Malicdan May Christine V., 野口 悟
    49 巻 (2009) 11 号 p. 852-855
    公開日: 2009/12/28
    ジャーナル フリー
    Distal myopathy with rimmed vacuoles (DMRV), also called hereditary inclusion body myopathy, is an autosomal recessive disorder caused by homozygous or compound heterozygous missense mutations in GNE which encodes a protein with two enzymatic activities in sialic acid biosynthesis: UDP-GlcNAc 2-epimerase and ManNAc kinase. The disease starts from 15-40 years and is slowly progressive. DMRV preferentially affects tibialis anterior and hamstrings muscles, and has characteristic findings in muscle pathology which include rimmed vacuoles, tubulofilamentous inclusions, deposition of amyloid, and phosphorylated tau. We generated DMRV mice (Gne-/-hGNE D176V-Tg) by crossmating Gne knock-out heterozygous mouse and human GNE p.D176V transgenic mouse. This model mouse recapitulates DMRV clinically, pathologically, and biochemically by developing muscle weakness and atrophy from 21 weeks, amyloid deposition from 31 weeks, and rimmed vacuoles and phosphorylated tau from 41 weeks while having lifelong hyposialylation. We gave three types of GNE metabolites, ManNAc, NeuAc and sialyllactose, to DMRV mice orally from 15 weeks until 55 weeks of age. Sialic acid supplementation almost completely precluded the disease and virtually no sign of DMRV was seen even at 55 weeks of age, indicating that decreased sialic acid is the cause of myopathic phenotype and sialic acid supplementation can prevent the disease process.
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  • 武田 伸一
    49 巻 (2009) 11 号 p. 856-858
    公開日: 2009/12/28
    ジャーナル フリー
    Duchenne muscular dystrophy (DMD) is caused by the lack of dystrophin protein at the sarcolemma. Exon skipping by antisense oligonucleotides is a novel method to restore the reading frame of the mutated DMD gene, and rescue dystrophin production. We recently reported that systemic delivery of Morpholino antisense oligonucleotides targeting exon 6 and 8 of the canine DMD gene, efficiently recovered functional dystrophin proteins at the sarcolamma of dystrophic dogs, and improved performance of affected dogs without serious side effects (Yokota et al., Ann Neurol. 65 (6): 667-676, 2009). To optimize therapeutic antisense Morpholinos for more frequent mutations of the DMD gene, we designed antisense Morpholinos targeting exon 51 of the mouse DMD gene, and injected them separately or in combination into the muscles of mdx52 mice, in which exon 52 has been deleted by a gene targeting technique (Araki et al., 1997). We also tried systemic delivery of antisense Morpholino to skip exon 51 in mdx52 mice. It is important to verify the effectiveness and side effects of antisense Morpholino in experimental animal models such as dystrophic dogs or mdx52 mice, before clinical trials in DMD patients.
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  • 戸田 達史
    49 巻 (2009) 11 号 p. 859-862
    公開日: 2009/12/28
    ジャーナル フリー
    Hypoglycosylation and reduced laminin-binding activity of α-dystroglycan are common characteristics of dystroglycanopathy, which is a group of congenital and limb-girdle muscular dystrophies. We previously identified the genes for Fukuyama congenital muscular dystrophy (FCMD) and muscle-eye-brain disease (MEB). FCMD, caused by a mutation in the fukutin gene, is a severe form of dystroglycanopathy. Knock-in mice carrying the founder retrotransposal insertion exhibited hypoglycosylated α-dystroglycan; however, no signs of muscular dystrophy were observed. More sensitive methods detected minor levels of intact α-dystroglycan, and solid-phase assays determined laminin binding levels to be approximately 50% of normal. In contrast, intact α-dystroglycan is undetectable in the dystrophic Large mouse, and laminin-binding activity is markedly reduced. These data indicate that a small amount of intact α-dystroglycan is sufficient to maintain muscle cell integrity in knock-in mice, suggesting that the treatment of dystroglycanopathies might not require the full recovery of glycosylation. Transfer of fukutin into knock-in mice restored glycosylation of α-dystroglycan. Transfer of LARGE produced laminin-binding forms of α-dystroglycan in both knock-in mice and the POMGnT1 mutant mouse. These data suggest that even partial restoration of α-dystroglycan glycosylation and laminin-binding activity by replacing or augmenting glycosylation-related genes might effectively deter dystroglycanopathy progression and thus provide therapeutic benefits.
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  • 川井 充
    49 巻 (2009) 11 号 p. 863-866
    公開日: 2009/12/28
    ジャーナル フリー
    1987年のデュシェンヌ型筋ジストロフィーの原因タンパクの発見から20年あまりがたち,ようやくエクソンスキッピング,ストップコドンの読み飛ばし,ユートロフィンの過剰発現など原因に近いところを標的とする治療法が実現しようとしている.日本でも治療法開発の最終段階として臨床試験がが計画されている.この領域では臨床試験の経験が乏しいため,適切な治療効果測定法が確立していない.筋ジストロフィーでは有効な治療法とみとめられるためには標的となるの生物学的マーカーの改善の証明は当然のことであるが,筋量の増加,筋力の増加,ADLの改善,QOLの改善が証明されて本当に有用な治療法であると結論できる.筋ジス臨床研究班では2002年からこれらの評価法の開発に取り組んできた.また現在開発中の筋ジストロフィーの治療は特定の遺伝子変異を対象とするいわゆるテイラーメイドの治療であるため,すべての個人について遺伝子変異の種類と場所を特定できる体制を用意しなければならない.2009年国立精神・神経センターに遺伝子解析センターを設置したところである.また臨床試験を開始するとき充分な数の被験者を短期間に組み入れるのが困難であることが予想される.そのためあらかじめ臨床情報と遺伝情報をふくむ筋ジストロフィー患者登録システムREMUDY(Registry of Muscular Dystrophy)を発足させた.研究者や製薬企業にはプロトコールの対象となる患者数を,患者には治療法開発の最新情報を伝えることができ,希少疾患の臨床試験基盤整備の原形となることが期待される.
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シンポジウム6:神経難病および医療ネットワーク
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