Α-シヌクレイン

SNCA
PDBに登録されている構造
PDB	オルソログ検索: RCSB PDBe PDBj
PDBのIDコード一覧
	1XQ8, 2JN5, 2KKW, 2M55, 2X6M, 3Q25, 3Q26, 3Q27, 3Q28, 3Q29, 4BXL, 4R0U, 4R0W, 4RIK, 4RIL, 4ZNN, 5CRW, 2N0A
識別子
記号	SNCA, NACP, PARK1, PARK4, PD1, synuclein alpha
外部ID	OMIM: 163890 MGI: 1277151 HomoloGene: 293 GeneCards: SNCA
遺伝子の位置 (ヒト)
染色体	4番染色体 (ヒト)
終点	89,838,315 bp
遺伝子の位置 (マウス)
染色体	6番染色体 (マウス)
終点	60,806,839 bp
RNA発現パターン
	; ;
	さらなる参照発現データ
遺伝子オントロジー
分子機能	• calcium ion binding; • protein N-terminus binding; • ferrous iron binding; • phospholipid binding; • 金属イオン結合; • fatty acid binding; • 酸化還元酵素活性; • magnesium ion binding; • histone binding; • zinc ion binding; • cysteine-type endopeptidase inhibitor activity involved in apoptotic process; • 血漿タンパク結合; • kinesin binding; • tau protein binding; • 銅イオン結合; • microtubule binding; • alpha-tubulin binding; • phosphoprotein binding; • phospholipase D inhibitor activity; • beta-tubulin binding; • identical protein binding; • dynein complex binding; • Hsp70タンパク質結合; • cuprous ion binding; • 酵素結合; • protein domain specific binding; • phospholipase binding; • actin binding; • SNARE binding;
細胞の構成要素	• postsynapse; • 細胞質; • 細胞質基質; • 膜; • シナプス; • 細胞外領域; • ミトコンドリア; • actin cytoskeleton; • perinuclear region of cytoplasm; • 細胞骨格; • 細胞核; • rough endoplasmic reticulum; • リボソーム; • シナプス小胞; • mitochondrial respiratory chain complex I; • platelet alpha granule membrane; • 終末ボタン; • リソソーム; • ゴルジ体; • intracellular membrane-bounded organelle; • 成長円錐; • 細胞膜; • 神経繊維; • 細胞皮質; • 封入体; • nuclear outer membrane; • axon terminus; • 細胞結合; • cytoplasmic vesicle membrane; • 細胞外空間; • supramolecular fiber; • soma; • ミトコンドリア外膜; • ミトコンドリア内膜; • mitochondrial intermembrane space; • ミトコンドリアマトリックス; • presynapse; • synaptic vesicle membrane;
生物学的プロセス	• negative regulation of neuron apoptotic process; • negative regulation of norepinephrine uptake; • response to interleukin-1; • response to interferon-gamma; • regulation of glutamate secretion; • response to magnesium ion; • synaptic transmission, dopaminergic; • regulation of reactive oxygen species biosynthetic process; • positive regulation of protein serine/threonine kinase activity; • cellular response to epinephrine stimulus; • positive regulation of synaptic transmission; • cellular response to copper ion; • regulation of synaptic vesicle recycling; • activation of cysteine-type endopeptidase activity involved in apoptotic process; • response to cocaine; • positive regulation of glutathione peroxidase activity; • negative regulation of platelet-derived growth factor receptor signaling pathway; • negative regulation of serotonin uptake; • regulation of dopamine secretion; • regulation of long-term neuronal synaptic plasticity; • response to iron(II) ion; • behavioral response to cocaine; • 運動の調節; • adult locomotory behavior; • positive regulation of neurotransmitter secretion; • cellular response to fibroblast growth factor stimulus; • positive regulation of peptidyl-serine phosphorylation; • regulation of acyl-CoA biosynthetic process; • positive regulation of endocytosis; • synaptic vesicle endocytosis; • 興奮性シナプス後電位; • regulation of neuronal synaptic plasticity; • mitochondrial membrane organization; • negative regulation of mitochondrial electron transport, NADH to ubiquinone; • 化学的シナプス伝達; • negative regulation of protein phosphorylation; • negative regulation of exocytosis; • positive regulation of hydrogen peroxide catabolic process; • negative regulation of microtubule polymerization; • calcium ion homeostasis; • mitochondrial ATP synthesis coupled electron transport; • positive regulation of inositol phosphate biosynthetic process; • dopamine biosynthetic process; • synapse organization; • negative regulation of dopamine metabolic process; • positive regulation of release of sequestered calcium ion into cytosol; • negative regulation of apoptotic process; • regulation of reactive oxygen species metabolic process; • regulation of neurotransmitter secretion; • negative regulation of dopamine uptake involved in synaptic transmission; • negative regulation of transcription by RNA polymerase II; • microglial cell activation; • dopamine uptake involved in synaptic transmission; • リポ多糖への反応; • protein destabilization; • neutral lipid metabolic process; • negative regulation of thrombin-activated receptor signaling pathway; • membrane organization; • negative regulation of transporter activity; • negative regulation of cysteine-type endopeptidase activity involved in apoptotic process; • regulation of phospholipase activity; • negative regulation of chaperone-mediated autophagy; • 老化; • receptor internalization; • negative regulation of monooxygenase activity; • 脂肪酸代謝; • dopamine metabolic process; • regulation of neuron death; • positive regulation of apoptotic process; • synaptic vesicle transport; • cellular response to oxidative stress; • phospholipid metabolic process; • negative regulation of histone acetylation; • regulation of macrophage activation; • positive regulation of receptor recycling; • 長期増強; • アポトーシス; • supramolecular fiber organization; • regulation of presynapse assembly; • positive regulation of inflammatory response; • positive regulation of neuron death; • negative regulation of neuron death; • response to desipramine; • regulation of transmembrane transporter activity; • regulation of norepinephrine uptake; • synaptic vesicle exocytosis; • SNARE complex assembly; • positive regulation of exocytosis; • protein complex oligomerization; • protein tetramerization; • synaptic vesicle priming;
	出典:Amigo / QuickGO
オルソログ
	6622
	20617
	ENSG00000145335
	ENSMUSG00000025889
	P37840
	O55042
NM_000345; NM_001146054; NM_001146055; NM_007308; NM_001375285;
	NM_001375286; NM_001375287; NM_001375288; NM_001375290
	NM_001042451; NM_009221
NP_000336; NP_001139526; NP_001139527; NP_009292; NP_001362214;
	NP_001362215; NP_001362216; NP_001362217; NP_001362219
	NP_001035916; NP_033247
	ウィキデータ
閲覧/編集ヒト	閲覧/編集マウス

α-シヌクレイン (あるふぁ-しぬくれいん) はSNCA 遺伝子によってエンコードされるアミノ酸140残基からなるタンパク質^[5]^[6]^[7]。

概要 SNCA, PDBに登録されている構造 ...

閉じる

このタンパクの断片が、アルツハイマー病に蓄積するアミロイド中の (主な構成成分であるアミロイドベータとは別の) 成分として発見され、もとのタンパク質がNACP (Non-Abeta component precursor 非アミロイド成分の前駆体) と命名された。後にこれがシビレエイ属のシヌクレインタンパクと相同であることがわかり、ヒトα-シヌクレインと呼ばれるようになった。

α-シヌクレインの蓄積は、パーキンソン病をはじめとする神経変性疾患 (いわゆるシヌクレイノパチー) の原因とされている^[8]^[9]。

α-シヌクレインは主として神経組織内にみられる機能不明のタンパク質であり、細胞質中のタンパク質の約1%にのぼる^[10]。α-シヌクレインは主に大脳新皮質、海馬、黒質、視床および小脳に発現する。主として神経細胞内に存在するが、グリア細胞内でも見られる^[11]。メラニン細胞では、SNCA遺伝子の発現を小眼球症関連転写因子 (microphthalmia-associated transcription factor, MITF) が調節している可能性がある^[12]。

α-シヌクレインが哺乳類の神経細胞体の核周辺にも広く存在していることがわかっており、このタンパク質が核内で何らかの役割を果たしている可能性が考えられる^[13]。しかしむしろシナプス前終末で圧倒的に多くみられ、脂質二重膜に結合しあるいは細胞質中に遊離して存在するが^[14]^[15]、膜結合型のものは約15%程度にすぎない^[16]。

α-シヌクレインは神経細胞のミトコンドリア内部に局在することが明らかになってきた^[17]。嗅球、海馬、線条体、黒質、視床では細胞質・ミトコンドリア内部にともに高濃度のα-シヌクレインが存在するが、一方大脳皮質と小脳では細胞質には豊富に存在するもののミトコンドリア内部には少ない、あるいはほとんど存在しない^[18]。ミトコンドリア内部のα-シヌクレインが、内膜上に局在していること、そして濃度依存的にミトコンドリア呼吸鎖の複合体Iに対して阻害的に作用することもわかっている。これらのことから、もともとミトコンドリア内部でのα-シヌクレイン発現のしかたは脳内の部位によって異なり、この発現の程度が、ミトコンドリア機能に影響し、また神経変性を起こしやすくなる潜在的因子である可能性がある^[18]。

SNCA遺伝子の選択的スプライシングによって、少なくとも3種のアイソフォーム (アミノ酸残基の配列は多少異なるが、働きそのものは変わらないタンパク質en) が産生される^[9]。よく研究されている主要なものは140アミノ酸残基からなるアイソフォームで、遺伝子すべてが翻訳される。その他エクソン3が欠けたα-シヌクレイン126 (41-54残基がない) や、エクソン5を欠いたα-シヌクレイン112^[19] (103-130残基がない) などがある^[9]。

学習に伴うシナプス再構築の際に、α-シヌクレインのシナプス前終末における数が特異的に上方制御 (ある刺激によって遺伝子発現が加速し、タンパク質産生が増加する調節) される^[20]。α-シヌクレインはチューブリンと相互作用し^[8]、(タウタンパクのように) 微小管結合タンパクとなりうる活性を持つことが示されている^[21]。

SNAREタンパク質複合体 (神経伝達物質放出において、シナプス小胞と細胞膜の融合にかかわる物質) の形成に際して、α-シヌクレインが分子シャペロンとして働いている可能性が示唆されている^[22]^[23]。特に、N末端ドメインで細胞膜のリン脂質と、C末端ドメインでシナプトブレビン-2 (SNAREタンパクの一種) と同時に結合するが、これはシナプス活性化の際には特に重要である^[24]。α-シヌクレインが神経細胞のゴルジ装置や小胞輸送の機能にかかわっている、という証拠は増えつつある^[25]。

脂質膜との相互作用

α-シヌクレインと膜の相互関係や、膜の合成と再生へのかかわりについても証拠が蓄積されつつある。酵母ゲノムスクリーニングで、脂質代謝にかかわる酵素の中にα-シヌクレインの毒性を増強するものがあることもわかった^[26]。逆にα-シヌクレインの発現レベルは、脂質二重層内にある脂肪酸の、粘度と相対的な量に影響している^[27]。

α-シヌクレインは脂質膜の負に帯電した表面に直接結合し^[27]、単層小胞に結合した状態では伸展したαヘリックス構造をとる^[28]。また小さな小胞に結合する傾向があり^[29]、脂質膜に結合することによって二重膜構造を変化させ、小さな小胞を形成させるという複雑な効果を及ぼす^[30]。すなわち負の電荷をもつ小胞の膜を折り曲げて、大きな小胞から細い環を形成する^[31]。膜における抗酸化活性を持つ可能性も指摘されている^[32]。

α-シヌクレインの一次構造は、通常次の3つのドメインから構成される

第1-60残基：両親媒性のN末端領域で、共通配列 KTKEGV (リシン-スレオニン-リシン-グルタミン酸-グリシン-バリン) を含む11残基の不完全な7回繰り返しが中心である。この配列はアポリポタンパク質の脂質結合領域に相同で、αヘリックス構造をとりやすい^[33]。
61-95残基：この中間部は疎水性領域で、非アミロイド成分 (non-amyloid component NAC) と呼ばれるタンパク凝集する部分である^[5]。
96-140残基：酸性度が高くプロリンを豊富に含む領域で、特定の構造をとらない。ある種のキナーゼによるチロシン125とセリン129のリン酸化が、α-シヌクレインの機能調節に関与している^[34]^[35]^[36]。

インビトロでα-シヌクレインをインキュベートする (恒温に保つ) と、自己分解して低分子量の様々な断片を生成することがわかる (高速液体クロマトグラフィー、高分解能イオン移動度質量分析器を用いた検出による)^[37]。もとの14.46kDa (キロダルトン) のタンパクから多数の断片が生じることが分かっており、例えばC末端やN末端が切断されてできる12.16kDaの断片 (14-133アミノ酸残基) 、10.44kDaの断片 (40-140アミノ酸残基) およびC末端の断片である7.27kDa (72-140) がある)^[37]。7.27kDaの断片はNAC領域の大部分を含んでおり、未分解のα-シヌクレインに比べてずっと速く凝集する。これらの分解産物が生体内 (インビボ) でも、α-シヌクレイン凝集に対して仲介・補助的に働いている可能性がある。

α-シヌクレインは長らく可溶性の天然変性タンパク質であると考えられてきたが、変異のない場合は安定な折りたたまれた4量体を形成し、凝集抵抗性を持つと思われる知見が得られている^[38]。にもかかわらず、パーキンソン病・レビー小体型認知症^[39]・多系統萎縮症^[40]のような疾患では、レビー小体に代表される不溶性の原線維を形成するため、これらの疾患はシヌクレイノパチーと呼ばれる。α-シヌクレインはレビー小体中のフィラメントとして代表的な構造体だが、レビー小体中にタウタンパク質が存在したり^[41]、また同一封入体中にα-シヌクレインとタウタンパク質のフィラメントがそれぞれ集合して存在していることもある^[42]。病的なα-シヌクレインはまた、孤発性および家族性アルツハイマー病のどちらの場合にもみられる^[43]。

α-シヌクレインの凝集メカニズムについては、かなり不明な点が多いが、凝集の前駆体としてまずβ構造に富む中間構造物を形成し、その後レビー小体になるという証拠も存在する^[44]。天然変性、αヘリックス、βシートに富む構造のそれぞれが混在し、平衡状態にあることを示唆する1分子レベルの研究もある。凝集を促進することがわかっている条件 -A30P (30番目のアミノ酸がアラニンからプロリンに変化する) 点変異やイオン強度の上昇といった緩衝液の変化- の下では、平衡状態が移動してβ構造の量が著しく増加することから、β構造が病的な凝集に関与していることが考えられる^[45]。α-シヌクレイン凝集が関与する疾患に対する治療戦略は様々考えられるが、凝集の阻害物質を使用する方法は重要である。例えばクミンアルデヒドは、低分子ながらα-シヌクレインの原線維化を阻害することが示されている^[46]。エプスタイン・バール・ウイルスもこれらの病態に関与している^[47]。

家族性パーキンソン病の中に、α-シヌクレインをコードする遺伝子が変異している稀なタイプが存在する。A53T^[48] (53番目のアラニンがスレオニンに)、A30P^[49] (30番目のアラニンがプロリンに)、E46K^[50] (46番目のグルタミン酸がリシンに) の3つの点変異がこれまでに同定されているほか、遺伝子重複 (二重複、三重複) も家族性パーキンソン病の原因となることがわかっている^[51] (こちらの方が点変異よりも数は多い)。このように、α-シヌクレインの変異によってアミロイド類似の原線維形成が起こり、パーキンソン病の原因となることがある。

以前までの抗ユビキチン抗体に代わって、抗α-シヌクレイン抗体 (リン酸化α-シヌクレイン特異抗体) がレビー小体免疫染色のゴールドスタンダードとして用いられるようになっている^[52]。

α-シヌクレインの断片の中には、タウオパチー (タウタンパク質が原因となる疾患群) に関与しているものがある^[53]。

α-シヌクレインは、以下の分子と相互に作用する。

ドーパミン輸送体^[55]^[56]
パーキン^[57]^[58]：家族性パーキンソン病の原因となるリガーゼの一種
ホスホリパーゼD1^[59]
シンフィリン-1 (SNCAIP)^[60]^[61]^[62]^[63]
タウタンパク質^[64]^[65]
アミロイドベータタンパク質^[66]

コントゥルシ・テルメ - α-シヌクレインの遺伝子変異による家族性パーキンソン病の家系が存在するイタリアの村
TMAO - 凝集を抑制するオスモライト

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ウィキメディア・コモンズには、α-シヌクレインに関するメディアがあります。
alpha-Synuclein - MeSH・アメリカ国立医学図書館・生命科学用語シソーラス（英語）

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