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The Role of LRRK2 Kinase Activity in Cellular PD Models

Cookson, MR; Greggio, E; Lewis, P; (2008) The Role of LRRK2 Kinase Activity in Cellular PD Models. In: Parkinson's Disease. (pp. 423-431).

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Abstract

This chapter discusses the role of LRRK2 kinase activity in cellular Parkinson's disease (PD) models. The presence of two catalytic domains and at least two protein-protein interaction domains within the 2500 amino acid LRRK2 protein sequence is predicted. Four of these regions, which are assumed to be independently folded and would thus fulfill the definition of a protein domain, contain one or more mutations whose pathogenicity can be definitively assigned. The dominant mechanism of inheritance of LRRK2 mutations suggests that they are associated with a gain of function, which might be predicted to have detrimental effects. It is shown that overexpression of mutant LRRK2 increased cellular toxicity when expressed for 2 days in either SH-SY5Y neuroblastoma cells or primary cortical neurons. Overexpression of mutant LRRK2 caused condensed and fragmented nuclei, suggesting that mutated proteins can drive toxicity by triggering apoptosis. It is suggested that the cellular toxicity of mutant LRRK2 can be prevented or ameliorated by inactivation of the kinase domain and that this can be explored using cell models. © 2008 Elsevier Inc. All rights reserved.

Type: Book chapter
Title: The Role of LRRK2 Kinase Activity in Cellular PD Models
ISBN-13: 9780123740281
DOI: 10.1016/B978-0-12-374028-1.00032-4
URI: http://discovery.ucl.ac.uk/id/eprint/1553964
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