Jain, S.; (2007) Discovery and characterization of LRRK2: Gene responible for PARK8-linked Parkinson disease. Doctoral thesis , University of London.

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Abstract

Parkinson disease (PD) is an incurable movement disorder clinically characterized by resting tremor, bradykinesia and other cardinal features. A Japanese kindred with autosomal dominant PD showed linkage to a novel locus on chromosome 12pl 1.2-ql3.1, subsequently given the designation PARK8. A British family showed linkage to the same region on chromosome 12, encompassing PARK8, with a maximal LOD score of 3.55. Genes within a 1-LOD support interval were subsequently prioritized for sequencing. A tyrosine to cysteine substitution at amino acid 1699 (Y1699C) that segregated with disease in the British family was discovered in the gene LRRK2. Subsequent studies demonstrated that mutations within LRRK2 are the most common genetic cause of PD, accounting for approximately 2-3% of apparently sporadic PD, 7-8% of familial PD and as much as 40% of PD in North African Arabic populations. LRRK2 is large protein consisting of multiple protein interaction motifs as well as GTPase and kinase domains. Analysis of LRRK2 suggests it is largely cytoplasmic and mutations within LRRK2 increase aggregation formation, kinase activity and neuronal toxicity. Further investigation indicates LRRK2 is able to self interact, forming at least a dimer and may represent a potential mechanism for the aggregation of LRRK2. LRRK2 also interacts with fasciculation and elongation factor zeta 2 (FEZ2), a mammalian orthologue of the Caenorhabditis elegans UNC-76 protein, which is involved in the axonal outgrowth and synaptic organisation. Although the function of LRRK2 is unknown, therapies directed towards LRRK2 are likely to have a great clinical impact and may bring us closer to understanding the pathogenic processes underlying PD.

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