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α-Synuclein BAC transgenic mice exhibit RBD-like behaviour and hyposmia: a prodromal Parkinson’s disease model

Taguchi, Tomoyuki 京都大学 DOI:10.14989/doctor.k23089

2021.03.23

概要

パーキンソン病(PD)はドパミン神経変性と病的な α シヌクレイン(αS)の蓄積、すなわちレヴィ小体を病理学的特徴とする神経変性疾患であるが、詳細な病態機序は明らかではない。現在の診断は運動症状を基準にしており、診断時点で既にドパミン神経は 50%以上減少していることが判明している。よって疾患修飾療法(DMT)の開発のためには発症前駆期のバイオマーカーの確立と同時に、前駆期の病態を忠実に反映したモデル動物の作製が必要不可欠である。

αS 遺伝子(SNCA)の重複で極めて孤発性 PD と類似した家族性 PD を生じることが知られており、また A53T 変異をはじめとした SNCA の点変異は αS の凝集能に変化をもたらし PD 発症に関与すると考えられている。さらに PD のゲノムワイド関連解析(GWAS)でも SNCA に最も影響力のあるリスク一塩基多型(SNP)が存在することが報告されている。この様に αS の質的・量的な変化は家族性のみならず孤発性 PD の病態形成にも重要な役割を果たしていると考えられる。

αS 遺伝子重複家系を模したモデルマウス作製のために、細菌人工染色体(Bacterial Artificial Chromosome: BAC)を用いてヒト αS の遺伝子発現調整領域を含めた SNCA 遺伝子を導入し、その自然な発現パターンを再現したトランスジェニックマウス(wild-type SNCA BAC tg マウス)が作製されたが、このマウスではドパミン神経の脱落や PD 関連症状は認められなかった。

本研究では、PD をその前駆期から再現するモデルマウスを作製するため、SNCA BAC tg マウスを基盤として、αS の凝集性を高めるための A53T 変異を、さらに孤発性 PD のリスクを高めるとされる2つの一塩基多型と Rep1 領域の多型を導入した。この A53T SNCA BAC tg マウスは、自然な αS 発現パターンにより中等度の αS発現増加を示した。行動解析においては、運動症状は認められなかったものの、生後 5 ヶ月以降のポリソムノグラフィーでレム睡眠行動障害(REM sleep Behavior Disorder: RBD)の重要な特徴である REM without atonia を示し、9 ヶ月の時点で嗅覚低下を呈するなど、複数の PD 前駆症状を呈した。病理学的解析では PD 病理の好発部位である嗅球、大脳皮質、線条体、黒質などの領域に病的な αS である αS オリゴマーや不溶化・リン酸化 αS の蓄積を認め、RBD の責任病巣と考えられている脳幹のレム睡眠を調節する神経細胞群にも同様の所見を認めた。さらに黒質緻密部のドパミン神経細胞数は年齢依存的に減少し、生後 18 ヶ月で野生型と比較して 17.1%の減少を認めた。

本研究で作製した A53T SNCA BAC tg マウスは、年齢依存性のドパミン神経細胞死に加えて、RBD 様症状と嗅覚低下という複数の PD 前駆症状を示す、前駆期 PDのマウスモデルとなった。本マウスは PD 前駆期の病態メカニズム解明や DMT 開発に大きく貢献することが期待される。

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