tailieunhanh - Báo cáo khoa học: LRRK2 in Parkinson’s disease: function in cells and neurodegeneration

The detailed characterization of the function of leucine-rich repeat kinase 2 (LRRK2) may provide insight into the molecular basis of neurodegenera-tion in Parkinson’s disease (PD) because mutations in LRRK2 cause a phe-notype with strong overlap to typical late-onset disease and LRRK2 mutations are responsible for significant proportions of PD in some popu-lations. | MINIREVIEW LRRK2 in Parkinson s disease function in cells and neurodegeneration Philip J. Webber and Andrew B. West Department of Neurology Center for Neurodegeneration and ExperimentalTherapeutics University of Alabama at Birmingham AL USA Keywords dopaminergic cell death familialParkinson s disease GTPase leucine-rich repeat kinase 2 MAP-kinase neurodegeneration Parkinsonism programmed cell death protein self-assembly serine threonine protein kinase Correspondence A. B. West 1719 Sixth Avenue South Birmingham AL 35294 USA Tel 1 205 996 7697 1 205 996 7392 Fax 1 205 996 6580 E-mail abwest@ Received 30 May 2009 revised 7 August 2009 accepted 28 August 2009 doi The detailed characterization of the function of leucine-rich repeat kinase 2 LRRK2 may provide insight into the molecular basis of neurodegeneration in Parkinson s disease PD because mutations in LRRK2 cause a phenotype with strong overlap to typical late-onset disease and LRRK2 mutations are responsible for significant proportions of PD in some populations. The complexity of large multidomain protein kinases such as LRRK2 challenges traditional functional approaches although initial studies have successfully defined the basic mechanisms of enzyme activity with respect to the putative effects of pathogenic mutations on kinase activity. The role of LRRK2 in cells remains elusive with potential function in mitogen-activated protein kinase pathways protein translation control programmed cell death pathways and activity in cytoskeleton dynamics. The initial focus on LRRK2-kinase-dependent phenomena places emphasis on the discovery of LRRK2 kinase substrates although candidate substrates are so far confined to in vitro assays. Here hypothetical mechanisms for LRRK2-mediated cell death and kinase activation are proposed. As a promising target for neuroprotection strategies in PD in vitro and in vivo models that accurately demonstrate LRRK2 s function relevant to .