DISC1

2014年3月24日 (月) 14:26時点におけるKkubo (トーク | 投稿記録)による版

英語名

DISC1

同義語

Disrupted in schizophrenia 1、Disrupted-In-Schizophrenia 1、Disrupted-in-Schizophrenia-1、Disrupted-in-schizophrenia 1、DISC-1

要約

 DISC1遺伝子は、染色体1番と11番の間での転座を有する、スコットランドの精神疾患多発家系から見いだされた。この転座によって染色体1番上で2つの遺伝子が破壊されると考えられ、そのうちの1つがDISC1である。DISC1からは複数のアイソフォームが翻訳されるが、主なアイソフォームとして854アミノ酸からなるタンパク質をコードする。DISC1に結合する分子(DISC1 Interactome)として、微小管結合分子やシナプスにおけるシグナル伝達分子など、数多くの分子(GSK3β、NDEL1、PCM1、BBS、Girdin/KIAA1212、PDE4、KAL7、TNIKなど)が報告されている。DISC1は神経系において様々な機能を持つと考えられているが、その代表的な機能として、大脳新皮質や海馬の神経発達や、シナプスの制御が想定されている。

イントロダクション(背景、歴史的推移など)

 DISC1遺伝子は、染色体1番と11番の間で均衡型常染色体転座(1;11)(q42.1;q14.3)を遺伝的に有する、スコットランドの精神疾患が集積する家系から見いだされた[1][2]。この家系の転座をもつ保因者29名のうち、21名に精神疾患の診断がなされ、そのうち、統合失調症が7名、双極性障害が1名、大うつ病が10名であった[3](Fig. 1)。それに対し、この家系の転座を持たない38名については、5名に精神疾患の診断がなされ、そのうちわけは、1名がアルコール依存、1名は青年期の行為−情緒障害、3名が小うつ病と、精神疾患としては比較的軽度の診断であった[4](Fig. 1)。この家系での転座によって、染色体1番上の遺伝子が2つ破壊されると考えられ、その破壊される遺伝子はDISC1DISC2と名付けられた[5]。このうち、DISC1は、主なアイソフォームとして854アミノ酸からなるタンパク質をコードする。一方、DISC2DISC1とは逆方向のノンコーディングRNAをコードする。

 なお、この転座は、特定の精神疾患への罹患に直接結びつくのではなく、この転座によって、精神疾患罹患のリスクを高めるエンドフェノタイプが生じると考えられる。実際、この転座を持つ保因者では、同じ家系内の非保因者よりも事象関連電位P300の振幅が有意に低下するとの報告もある[6]

構造

 DISC1からは、複数のアイソフォームが翻訳され、ヒトの脳では、多種類以上の異なったスプライスバリアントが発現する[7]。そのうち主なアイソフォームとしては、13個のエクソンから、854アミノ酸からなるタンパク質が翻訳される。この全長のDISC1タンパク質は100 kDa前後の分子量を持ち、N 末領域とC末領域に大きく分けられる[8][9]。N末領域は、1〜350番目のアミノ酸残基からなり、他の分子との相同性が低い。C末領域は、350〜854番目のアミノ酸残基からなり、複数のαへリックス構造やコイルドーコイル構造(coiled-coil)を持つ(Fig. 2)。

 DISC1発見の契機となった、スコットランドの家系での染色体転座では、DISC1の597番目と598番目のアミノ酸の間で切断が起きる。この結果、C末を欠いた597番目のアミノ酸までのDISC1タンパク質が発現してドミナントネガティブ(dominant negative)体として働く可能性[10]や、C末を欠いたDISC1タンパク質は分解されて結果としてハプロインサフィシャンシー(Haploinsufficiency)となる可能性が考えられている[11]。最近、1番染色体と11番染色体の融合タンパク質DISC1 Fusion Partner 1 (DISC1FP1)/DISC1-Boymaw fusion proteinが生成される可能性も指摘されている[12][13][14]

 また、DISC1は二量体もしくはそれ以上の多量体(オリゴマー)を形成すると考えられている。その際に、DISC1同士は、403〜504番目のアミノ酸を用いて相互作用する[15]。加えて、C末の640-854番目のアミノ酸もオリゴマー形成に関与しているとされる[16]

 マウスのDISC1相同遺伝子(ortholog)としてクローニングされたDisc1は851アミノ酸をコードし、ヒトのDISC1と60%程度の相同性を持つ[17][18]。C57BL/6のマウス系統とは異なり、129のマウス系統ではエクソン5に25塩基の欠損があることが知られる[19][20]。他の系統のマウスにもこの25塩基の欠損を有するものがあるため、注意が必要である[21]。ただし、マウスでも複数のスプライスアイソフォームがあることが知られており、25塩基の欠損を有するマウス系統においてDISC1アイソフォームの多くは発現していると考えられている[22]


DISC1タンパク質に結合する分子

 DISC1は足場(scaffold)タンパク質、もしくは、ハブ(hub)タンパク質として機能すると考えられ、多くの結合分子(DISC1 interactome)が知られている[23][24]。これらの結合分子の探索がDISC1の機能の解明に大きな役割を果たしてきた。主な分子名を下に挙げる(分子名の後の数字は、報告されたDISC1上の結合部位[アミノ酸残基])(Fig.2も参照)。

Nuclear distribution element-like 1 (NDEL1/NUDEL) [802-835] [25][26][27][28]

Microtubule-associated protein 1A(MAP1A) [1-293] [29]

Fasciculation and elongation protein zeta-1 (FEZ) [446-633] [30]

Kendrin/pericentrin-B [446-533][31]

Phosphodiesterase type 4(PDE)[190-230、611-650など][32][33]

Kinesin-1のkinesin heavy chain [341-400] [34]

Growth factor receptor bound protein (Grb2) [730-733, 731-734][35]

Bardet-Biedl syndrome protein (BBS)1、 BBS4、BBS8 [394-600] [36][37]

Pericentriolar material 1 (PCM1) [1-348, 601-854] [38]

Glycogen synthase kinase 3β(GSK3β)[1-220、356-595] [39]

Girdin/KIAA1212 [1-361] [40][41]

Kalirin-7 (KAL7) [350-394] [42]

DIX domain containing 1 (DIXDC1) [592-852] [43]

TRAF2- and NCK- interacting protein kinase (TNIK) [335-347] [44]


発現(組織分布)

 DISC1のmRNAは成体において、脳に加えて、心臓、胎盤、膵臓などに発現している[45]。成熟マウスでは、Disc1のmRNAは脳内に広く分布しており、海馬、小脳、大脳新皮質、嗅球にも発現が見られる[46]。発生段階のマウスの脳において、DISC1の免疫反応は大脳皮質、嗅球[47]や海馬[48]に認められる。脳のなかで、DISC1は神経細胞のみならず、アストロサイト、オリゴデンドロサイト、ミクログリアといったグリア系の細胞でも発現している[49][50][51]


細胞内局在

DISC1は、発達段階の神経細胞において、NDEL1/NUDEL、Lissencephaly 1(LIS1)、14-3-3、dynactin、kendrinなどと結合/複合体を形成して、中心体(centrosome、microtubule-organizing center[MTOC]としても知られる)や微小管(microtubule)に存在する[52] [53][54]。また、Kinesin-1、Grb2と結合して軸索内を成長円錐(Growth Cone)に運ばれる[55][56]

 より成熟した神経細胞において、DISC1はPSD-95/ Kalirin-7と複合体を作り、シナプスに存在している[57]。シナプスではPDE4やTNIKとも結合する[58][59]。DISC1は興奮性のシナプスとともに、抑制性のシナプスにも局在する[60]

 DISC1のN末には核移行シグナル(nuclear localization signal、NLS)モチーフが存在し、少なくともDISC1の一部は核内に存在する[61]。DISC1のミトコンドリアへの局在も報告されている[62][63][64]


機能

 DISC1の結合タンパク質や細胞内局在から示されるように、DISC1は神経系において多彩な機能を有していると考えられる。なかでも代表的な機能として、神経発達とシナプスの制御が挙げられる[65][66][67]

 上記の細胞内局在のうち、中心体や微小管、成長円錐への局在は、神経細胞の増殖や移動、樹状突起形成、軸索伸長といった、DISC1の神経発生過程での機能を示唆する。実際に、発達段階でのDISC1の機能阻害により、神経細胞の増殖の低下/早熟な神経への分化[68][69]、大脳新皮質[70][71][72]と海馬[73][74]の神経細胞移動の遅れ、樹状突起形成の障害[75]、軸索伸長の障害[76][77][78][79]が起きることが報告されている。ただし、成体での海馬歯状回における、新生神経細胞については、DISC1の機能阻害により、むしろ神経細胞の過剰な移動が生じる[80][81][82]。この過剰な移動は神経細胞層への組み込み(integration)の阻害を反映する可能性もある[83]

 また、シナプスへの局在やシナプス関連分子との結合から、DISC1はシナプスの維持や制御に関わると考えられている。DISC1の機能阻害により、短期的には樹状突起スパインの数と大きさが増加し、長期的にはスパインが小さくなる[84]。この際、DISC1は、Kalirin-7(Rac1のGDP/GTP exchange factor、GEF)と結合してNMDA受容体の活性化によって起きるRac1の活性化を調節してシナプスを制御する。DISC1はTNIKとの結合によってもシナプスの維持に関わると考えられている[85]


DISC1の修飾と機能への影響

 他の分子との結合の調節に、DISC1の翻訳後修飾が関与することがある。例えば、マウスDISC1の710番目のセリン(S710、ヒトDISC1の713番目のセリンに相当)のリン酸化によって、結合分子が変化する[86]。増殖中の神経前駆細胞において、S710がリン酸化されていないときは、DISC1はGSK3βに結合してGSK3βの活性を抑制する。一方、分裂後の神経細胞において、S710がリン酸化されると、DISC1はBBS1に結合して中心体や微小管に分布し、神経細胞移動に関わる。このように、DISC1のリン酸化の制御によって、前駆細胞の分裂から神経細胞移動へ、発生段階のスイッチが行われると考えられる[87]

関連語

 エンドフェノタイプ、統合失調症、双極性障害、大うつ病、GSK-3β


参考文献

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(担当者 久保 健一郎、神谷 篤、編集者 加藤 忠史)