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BioMed Research International - Volume 2015 2015, Article ID 678701, 6 pages -

Research ArticleDepartment of Neurology, National Neuroscience Institute, 7 Hospital Drive, Outram Road, Singapore 169611

Received 20 September 2014; Revised 19 January 2015; Accepted 26 January 2015

Academic Editor: Hiroyuki Tomiyama

Copyright © 2015 Fathima Shaffra Refai et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Mutations in the leucine-rich repeat kinase 2 LRRK2 have been known to be a major genetic component affecting Parkinson’s disease PD. However, the pathogenicity of many of the LRRK2 variants is unclear because they have been detected in single patients or also in patients and controls. Here, we selected 5 exonic variants L1165P, T1410M, M1646T, L2063X, and Y2189C from each of the protein domain of LRRK2 and analysed their possible association with pathogenicity using in vitro functional assays. Point mutations representing each of these variants were incorporated into the LRRK2 gene, and functional aspects such as the percentage of cell survival upon application of stress and kinase activity were measured. Our results showed that all 5 variants had a significantly negative effect on the survival of cells, in both presence and absence of stress, as compared to the wild-type. In addition, there was also a slight increase in kinase activity in most of the variants in comparison to the wild-type. A negative correlation between cell survival and kinase activity was observed. These data suggest that most of the variants despite being located in different domains of LRRK2 appear to exert a potential pathogenic effect possibly through an increased kinase activity, supporting a gain of function mechanism.

Autor: Fathima Shaffra Refai, Shin Hui Ng, and Eng-King Tan

Fuente: https://www.hindawi.com/


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