α-シヌクレイン(SNCA)遺伝子とパーキンソン病

The Relationship between Alpha-synuclein and Parkinson's Disease

はじめに

　パーキンソン病（Parkinson's disease: PD）の病理学的診断に不可欠な細胞質内封入体としてLewy小体がある。近年，封入体形成と疾患発症との関連が言われており，封入体そのものは神経保護的な作用を持つことが指摘され，monomer→protofibril→fibril→Lewy小体のカスケードの上流において毒性があると考えられている。この封入体の主要構成成分の1つにα-シヌクレインが報告されており，この蛋白の機能解析はPDの本質的原因解明へ通ずることが考えられている。本稿では，α-シヌクレインの分子構造と，missense mutationの臨床病態，そして世界中に分布することが推定されるα-シヌクレインの重複に関して，自験例も含めて解説する。

Abstract

　Alpha-synuclein(SNCA) is a major component of Lewy bodies.　Lewy bodies were appeared in some neurodegenerative disorders known as Alzheimer's disease or Parkinson's disease.　Recently SNCA multiplications were reported in several autosomal familial Parkinson's disease (ADPD).　In two triplication pedigree,the double expression level of alpha-synuclein was reported in both peripheral blood and brain.　And the some affected patients in SNCA multiplication family also had more severe prognosis than sporadic patients.　They were suffered from cognitive decline and severe parkinsonism.　Mainly triplication patients were showed severe prognosis compared to duplication patients.　They had young onset and non-responsiveness to levodopa.　On the other hand,duplication patients had milder course similar with sporadic cases.　These analysis were suggested that the gain of function mechanism on SNCA could cause severe dementia like diffuse Lewy bodies and high amount of Lewy bodies in brain.　And the differences of length between triplication and duplication also might be influenced on clinical aspects.　In this review,we described about the clinical and genetic aspects of alpha-synuclein,not only SNCA multiplication but also mis-sense mutation of SNCA.