. Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron. 2004 Nov 18;44(4) PubMed.

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  1. The identification of genes for Mendelian forms of Parkinson disease (PD) has greatly advanced the understanding of the molecular pathogenesis of this common neurodegenerative disorder. The discovery of mutations in the gene for α-synuclein (SNCA; PARK1) in dominantly inherited PD and of three genes, parkin, DJ1, PINK1 (PARK2, 6, and 7, respectively) causing recessive, early-onset parkinsonism have been major milestones in recent years.

    A gene causing an autosomal-dominant, late-onset form of parkinsonism, originally mapped in a large Japanese family, PARK8 on chromosome 12q12, (Funayama et al., 2002), is the latest addition to this list, and may prove to be particularly interesting.

    Recently, our group, consisting of researchers at the Hertie-Institute for Clinical Brain Research in Tubingen, Germany, the GSF Research Center for Environment and Health in Neuherberg, Germany, and at the Mayo Clinic, Jacksonville, Florida, showed that two large families with autosomal-dominant late-onset parkinsonism (Families A and D) are linked to the PARK8 locus (OMIM# 607060) (Zimprich et al., 2004).

    In these kindreds, we identified missense mutations in a novel gene, leucine-rich repeat kinase 2 (LRRK2), which cosegregate with disease (Family A; Y1699C, 5096A>G and Family D; R1441C, 4321C>T). Screening of 44 additional families revealed two further missense and one putative splice site mutation, all in families with typical late-onset PD compatible with a dominant transmission (I1122V; 3364A>G), (I2020T; 6059T>C), and (L1114L; 3342A>G). Affected individuals in one additional family were found to carry the same mutation as Family D (R1441C, 4321C>T).

    We determined the coding sequence and exon composition of LRRK2 and found that the gene spans a genomic region of 144 kb, with 51 exons encoding 2,527 amino acids. Our sequence analysis also revealed several intronic, silent, and coding polymorphisms that do not appear to segregate with disease and which are found at an appreciable frequency in controls (>one percent), including R1514Q; 4541G>A, M1646T; 4937T>C, and N2081D; 6241A>G. The LRRK2-sequence, and its variants are deposited in Genbank under accession number AY792511. We have since established that coding changes are relatively frequent, and penetrant, in autosomal dominant, familial, and sporadic, community-based, late-onset Parkinson disease in the U.S. (>1.5% of cases, unpublished data). Our report appears in the November 18 issue of Neuron. In the same issue, Paisan-Ruiz et al. publish two mutations, one in a British family, and one in a group of related Basque families in the same gene, which they named dardarin. Interestingly, the mutation they found in the British family is identical to the one found by us in Family A, while the founder mutation in the Basque families affects the very same nucleotide that is altered in Family D, though it causes a different amino-acid change. It should be noted that the designation of the position of the mutations differs in the two publications, since Paisan-Ruiz et al. have used the in silico prediction of the gene, which is incomplete, rather than the actual cDNA sequence. LRRK2 is a novel member of the recently defined ROCO protein family (Bosgraaf and Van Haastert, 2003) as predicted in silico by the presence of two conserved domains, (i) a ROC (Ras in complex proteins) domain that belongs to the Ras/GTPase superfamily and a COR domain (C-terminal of Roc) that is also characteristic for this protein family. Three further conserved domains can be identified: (i) a leucine-rich repeat (LRR), (ii) a tyrosine kinase catalytic domain (TyrKc), and (iii) a WD40 domain. The sequence of this newly identified gene, therefore, suggests multiple functions; it is unclear which domain or domains are related to neurodegeneration. Remarkably, we found that affected individuals with LRRK2 mutations exhibit strikingly variable pathologic changes, representing aspects of several of the major neurodegenerative diseases. The common feature of the neuropathology of six affected individuals from families A and D who have come to autopsy is neuronal loss and gliosis in the substantia nigra, which is the likely pathologic substrate of parkinsonism. In three of the individuals (two from Family A and one from Family D) there was non-specific loss of dopaminergic neurons, with ubiquitin-immunoreactive cytoplasmic and nuclear inclusions. Two individuals (both from Family D) had Lewy body pathology. In one case, Lewy bodies were relatively restricted to brainstem nuclei as in typical PD. In the other case, there was widespread α-synuclein pathology, including Lewy bodies and Lewy neurites, in a pattern typical of diffuse Lewy body disease. In the final individual, there was tau immunoreactive neuronal and glial lesions that morphologically resembled PSP.

    Pathogenic mutations in LRRK2 thus appear to be central to etiology of not just one, but several neurodegenerative diseases, including those associated with α-synuclein and tau pathology, and clinical parkinsonism.

    View all comments by Thomas Gasser

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  1. PARK8 is Cloned: Introducing…"Dardarin"