PARK8(LRRK2)の臨床分子遺伝学

Clinical Molecular Genetics for PARK8 (LRRK2)

はじめに

　パーキンソン病（Parkinson's disease: PD）は安静時振戦，無動，固縮および姿勢反射障害を主要症候とし，アルツハイマー病に次いで2番目に多いとされる神経変性疾患である。加齢とともにPDの頻度は上昇し，65歳までで～1％，65歳以上で～3％，85歳以上で～5％の頻度とも報告されている^1，2）。その本態は黒質でのドパミンニューロンの変性脱落であり，Lewy小体の出現がPDの病理学的診断の指標とされてきている。

　PDのほとんどは孤発性で，約5～10％に遺伝性PD（FPD）を認める。PDの原因はいまだに明らかではないが，遺伝的因子と環境因子の相互作用による多因子疾患と考えられている。遺伝的因子に関し，これまで常染色体優性遺伝性PD（ADPD）のうちα-synuclein^3），UCH-L1^4），LRRK2^5，6），常染色体劣性遺伝性PD（ARPD）のうちparkin^7），PINK1^8），DJ-1^9），と計6つが確立した原因遺伝子として報告されている。最近，PDと臨床像を少し異にするが，常染色体劣性遺伝性のPARK9もATP13A2遺伝子変異によることが報告され^10），ここ数年でPINK1, LRRK2, ATP13A2と3つの原因遺伝子が次々に同定されており，PD関連疾患に対する遺伝学的アプローチはますます盛んになってきている。本稿では最新の知見を含め，PARK8^11）の原因遺伝子として同定されたLRRK2の臨床分子遺伝学について概説したい。

Abstract

　Parkinson's disease (PD) is an etiologically heterogeneous disorder characterized by parkinsonism (bradykinesia,resting tremor,rigidity,and postural instability) with good response to L-dopa.　PD is the second most prevalent neurodegenerative disorder after Alzheimer disease.　Although the majority of PD cases are sporadic,5-10 % of PD is monogenic form of PD as familial PD (FPD).　Multifactorial genetic-environmental interaction has been thought in PD pathogenesis,although these interactions are still poorly understood.　In 2004,LRRK2 was identified as the causative gene for PARK8 originally mapped in the large Japanese Sagamihara family with late-onset autosomal dominant PD (ADPD).　Patients with LRRK2 mutations account for approximately 2-13% of ADPD and 0.5-3% of sporadic PD. Genetically,LRRK2 mutations have been distributed worldwide with some ethnic differences by single founder effect such as G2019S,R1441G,and G2385R variants.　LRRK2 G2385R was reported to be a risk factor for sporadic PD in Asia.　Clinically,most patients with LRRK2 mutations develop typical idiopathic PD,however,variable clinical features and pathologies such as diffuse Lewy body disease,multiple system atrophy,progressive supranuclear palsy,and amyotrophic lateral sclerosis have been reported.　Although Lewy bodies have been considered as a pathological hallmark for sporadic PD classically,some FPD and sporadic PD patients with heterozygous LRRK2 mutations or homozygous parkin mutations have no Lewy bodies.　On the other hand,LRRK2 was reported as a component of Lewy bodies.　Based on the variability,multifunction of LRRK2 such as phosphorylation of other proteins,especially,alpha-synuclein and tau,have been suggested.　As interaction of Parkin and LRRK2 was reported,interaction and intersection among the autosomal-recessive or autosomal-dominant PD proteins could be involved in some common pathways,and LRRK2 may play an important role as a key FPD gene product.　Identification of PARK8 and LRRK2 has given meaningful insights in not only PD but also numerous neurodegenerative disorders such as synucleinopathies and tauopathies with or without Lewy bodies.