SAGE KE Bulletin Board

First functional data on LRRK2

13 December 2005

Daniela M. Vogt Weisenhorn

Comment on

West et al. (2005) Parkinson´s disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. PNAS 102 (46): 16842 -16847

Gloeckner et al. (2005) The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity. HMG advance access Dec. 1, 2005-12-12

With the identification of several genes implicated in Mendelian forms of one of the major age-related neurological diseases, that is Parkinson´s disease, our understanding of the pathogenic mechanisms of this disorder has advanced significantly (Corti et al., 2005; Gasser et al., 2005). Until recently alpha-synuclein was considered to be the major and only gene responsible for autosomal dominant forms. However, with the discovery of leucin rich repeat kinase 2 (LRRK2) in late 2004 a much more frequently affected gene has been identified (Paisan-Ruiz et al., 2004; Zimprich et al., 2004a). Mutations in LRRK2 have now been reported to account for 5->10% of familial cases of the disease exhibiting a phenotype, pathology and in vivo imaging similar to idiopathic, late-onset Parkinson’s disease (Adams et al., 2005; Berg et al., 2005; Khan et al., 2005). The predicted protein (285 KD) belongs to the Roco protein family and consists of multiple domains: N-terminal leucine rich repeats, a GTPase domain Roc (Ras of complex proteins), a COR domain (C-terminal of Roc), a MAP kinase kinase kinase domain (MAPKKK) and C-terminal WD40 repeats. Interestingly, all but one of the 16 identified LRRK2 mutations are missense and all but 2 are located in functional domains of the protein. In order to understand the role of these mutations in the etiology of Parkinson´s disease and the placement of LRRK2 into biochemical pathways the major challenge is now to elucidate the normal and pathological functions of LRRK2. The articles of West et al, and Gloeckner et al. both are the first ones tackling this issue. Both report that LRRK2 is localised in the cytoplasm and associated with cellular membrane structures. In addition, using a GFP-tagged LRRK2 Gloeckner et al. found LRRK2 differentially and partially localised to mitochondria, ER and Golgi and interestingly quite strongly with b-tubulin. Most importantly, however, both reports demonstrate that LRRK2 exhibits autokinase activity, which is even increased in disease associated mutants. This finding hints towards a gain-of-function of pathogenic LRRK2. Still, it has to be kept in mind that in both reports the increased phosphorylation activity was not demonstrated on physiological relevant substrates, which still have to be identified. Nevertheless, if indeed the critical feature of LRRK2 function in the pathogenesis of Parkinson´s disease is associated with increased kinase activity, it could explain the autosomal-dominant inheritance pattern of LRRK2 mutations. Furthermore, this finding nourishes the hope that the comparably easy and straightforward development and/or identification of small therapeutic molecules which inhibit the kinase activity of LRRK2 may lead to an effective therapy of at least this common familial form of Parkinson´s disease – a therapeutic approach already successfully applied in treatement of cancer in which oncogenic kinase variants have been identified (Krause et al. 2005).

Adams JR, vanNetten H, Schulzer M, Mak E, McKenzie J, Strongosky A, et al. PET in LRRK2 mutations: comparison to sporadic Parkinson’s disease and evidence for presymptomatic compensation. Brain 2005. Epub ahead of print.

Berg D, Schweitzer K, Leitner P, et al. Type and frequency of mutations in the LRRK2 gene in familial and sporadic Parkinson’s disease. Brain 2005. In press.

Corti O, Hampe C, Darios F, Ibanez P, Ruberg M, Brice A. Parkinson’s disease: from causes to mechanisms. [Review]. C R Biol 2005; 328: 131–42

Gasser T. Genetics of Parkinson’s disease. [Review]. Curr Opin Neurol 2005; 18: 363–9.

Khan NL, Jain S, Lynch JM et al. Mutations in the gene LRRK2 encoding dardarin (PARK8) cause familial Parkinson’s disease: clinical, pathological, olfactory and functional imaging and genetic data. Brain 2005. In press.

Krause DS and Van Etten RA (2005) Tyrosine Kinases as Targets for Cancer Therapy. N Engl J Med. 353(2):172-87

Paisan-Ruiz C, Jain S, Evans EW, Gilks WP, Simon J, van der Brug M, et al. Cloning of the gene containing mutations that cause PARK8-linked Parkinson’s disease. Neuron 2004; 44: 595–600.

Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, Lincoln S, et al. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 2004a; 44: 601–7.

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