A Novel Kinase Implicated in Parkinson's Disease

Abstract

Two groups have implicated a gene encoding a putative kinase of unknown function in familial Parkinson's disease. Parkinson's disease, the second most common neurodegenerative disease, results from the degeneration of a set of dopaminergic neurons. The recent identification of several genes implicated in familial forms of parkinsonism has begun to provide clues to the underlying molecular mechanisms. Two groups identified a novel gene at the PARK8 locus on chromosome 12p11.2-q13.1 that had previously been linked to an autosomal-dominant, late-onset, familial form of parkinsonism (see Preview by Shen). Paisán-Ruíz et al. identified a missense mutation within a kinase-domain-containing transcript that segregated with the disease in four families, as well as a different mutation in the same gene in a fifth family. Zimprich et al. identified six segregating mutations in the same gene; two of these affected the same amino acid residues found in the Paisán-Ruíz study. The affected gene, which has been named LRRK2 ( leucine-rich repeat kinase 2 , with the protein called LRRK2 by Zimprich et al. and dardarin by Paisán-Ruíz et al. ), encodes a 2527-amino acid protein. It is predicted to contain a leucine-rich domain, a Ras superfamily domain (Roc, for Ras in complex proteins), a COR (C-terminal of Roc) domain, a nonreceptor tyrosine kinase domain, and a WD40 domain. Although the role of LRRK2-dardarin remains unknown, it likely functions as a kinase, and identification of its functions and substrates may help unravel the molecular underpinning of Parkinson's disease. C. Paisán-Ruíz, S. Jain, E. W. Evans, W. P. Gilks, J. Simón, M. van der Brug, A. López de Munain, S. Aparicio, A. Martinez Gil, N. Khan, J. Johnson, J. Martinez, D. Nicholl, I. M. Carrera, A. Saénz Peña, R. de Silva, A. Lees, J. F. Martí-Massó, J. Pérez-Tur, N. W. Wood, A. B. Singleton, Cloning of the gene containing mutations that cause PARK8 -linked Parkinson's disease. Neuron 44 , 595-600 (2004). [Online Journal] A. Zimprich, S. Biskop, P. Leitner, P. Lichtner, M. Farrer, S. Lincoln, J. Kachergus, M. Hulihan, R. J. Uitti, D. B. Calne, A. J. Stoessl, R. F. Pfeiffer, N. Patenge, I. Carballo Carbajal, P. Vieregge, F. Asmus, B. Müller-Myhsok, D. W. Dickson, T. Meitinger, T. M. Strom, Z. K. Wszolek, T. Gasser, Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44 , 601-607 (2004). [Online Journal] J. Shen, Protein kinases linked to the pathogenesis of Parkinson's disease. Neuron 44 , 575-577 (2004). [Online Journal]