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Session III : Protein kinase cascades as therapeutic targets Poster III, 65
Leukocyte mitogen activated protein kinase cascade activity associated with the LRRK2
G2019S mutation and Parkinson's disease
Linda R. White1, Sylvia N. Kvam2, Mathias Toft1,3, Matthew Farrer3, Jan O. Aasly2
1Department of Neuroscience, Norwegian University of Science and Technology,
2Department of Neurology, University Hospital of Trondheim, N-7006 Trondheim,
Norway, and 3Department of Neuroscience, Mayo Clinic College of Medicine,
Jacksonville, Florida, USA. E-mail: linda.white@ntnu.no
Several pathogenic mutations in the leucine-rich repeat kinase 2 (LRRK2, Park8) gene have
now been identified in connection with familial and sporadic parkinsonism. Of these, the
substitution 6055G>A is the hitherto most common cause of genetically-related Parkinson's
disease (PD) to be found, accounting for over 2 % of PD patients in Norway (Aasly et al.,
Ann Neurol 2005;57:762-5). The mutation is autosomal dominant, the clinical features
including asymmetric resting tremor, bradykinesia and rigidity, with a good response to
levodopa treatment. It is thus indistinguishable from idiopathic PD. LRRK2 is a large,
multidomain protein, and the 6055G>A mutation results in a single amino acid substitution
(G2019S) in the mitogen-activated protein kinase kinase kinase (MAPKKK) domain, at the
start of the kinase activation site (a highly-conserved region). This is therefore expected to
affect enzyme activity. Since PD develops in the later decades of life, it is likely that changes
in MAPK cascades attributable to the mutation might be identifiable prior to disease
development, and in tissues other than the brain's dopaminergic system. We have therefore
isolated leukocytes from the blood of Norwegian patients bearing the Park8 G2019S mutation
and diagnosed as suffering from PD, as well as from patients identified as mutation carriers,
but who have not yet developed any movement disorder, and from relatives identified as not
carrying the mutation. These groups have been compared with a positive control group
(patients with typical PD of no known cause, genetic or otherwise (idiopathic PD)), and age
and sex-matched healthy controls. The phosphorylation of proteins central to MAPKmodulated
signal transduction has been assayed in these samples by protein microarray and
ELISA, and highly significant differences between the groups identified.
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