パーキンソン病の分子遺伝学

Molecular genetics of Parkinson's disease

　Parkinson病（PD）は，一部はMendelの遺伝形式に則って発症するが，症例の90％以上は孤発性として認知される。発症機序としては，遺伝要因と環境要因を基盤として，ミトコンドリア機能障害，炎症反応，酸化ストレス障害により，アポトーシスによるドパミン細胞死が惹起され発症に至ると考えられている。近年，Mendel遺伝性PDの原因遺伝子として6つの遺伝子が同定され，新たにユビキチン・プロテアソーム系の病態への関与が明らかになった。孤発性PDは多因子疾患であり，機能的候補遺伝子について関連解析がなされているものの，確実な疾患感受性遺伝子は発見されていない。2001年に罹患同胞対によるノンパラメトリック連鎖解析が発表され，連鎖領域が示された。現在では，ヒトゲノム解析の進展を受けて，ゲノムワイドな関連解析が試みられている。

　Parkinson's disease（PD）is the second most common neurodegenerative disorder in the world. The occurrence of PD is largely sporadic, while several families with Mendelian segregation of PD have been reported. PD is thought to be caused by mitochondrial dysfunction, oxidative stress and inflammation due to multiple genetic and environmental factors, resulting in the apoptosis of dopaminergic cells. Six causal genes for Mendelian inherited PD have been identified to date, which indicate the importance of the ubiquitin-proteasome pathway in the molecular pathogenesis of dopaminergic cell death. Recent studies have also indicated the involvement of genetic factors in the pathogenesis of sporadic PD.

　Many association studies on candidate genes have examined the relationship between PD and polymorphisms；however, SNPs that influence sporadic PD as strongly as APOE-e4 influences Alzheimer disease have not been identified. Since 2001, significant linkage to several loci have been reported in samples of affected sibling pairs.

　With the recent advances in human genome analyses, we are now able to examine the whole genome for susceptibility genes for PD.

　At present, genome-wide association studies are being performed to identify susceptibility genes and to establish tailor-made medicine for PD.