[Clinical molecular genetics for PARK8 (LRRK2)].Brain Nerve. 2007 Aug; 59(8):839-50.BN
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.