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Insights into the Influence of Specific Splicing Events on the Structural Organization of LRRK2

Authors :
Dimitrios Vlachakis
Nikolaos E. Labrou
Costas Iliopoulos
John Hardy
Patrick A. Lewis
Hardy Rideout
Daniah Trabzuni
Source :
International Journal of Molecular Sciences, Vol 19, Iss 9, p 2784 (2018)
Publication Year :
2018
Publisher :
MDPI AG, 2018.

Abstract

Leucine-rich repeat kinase 2 (LRRK2) is a large protein of unclear function. Rare mutations in the LRRK2 gene cause familial Parkinson’s disease (PD) and inflammatory bowel disease. Genome-wide association studies (GWAS) have revealed significant association of the abovementioned diseases at the LRRK2 locus. Cell and systems biology research has led to potential roles that LRRK2 may have in PD pathogenesis, especially the kinase domain (KIN). Previous human expression studies showed evidence of mRNA expression and splicing patterns that may contribute to our understanding of the function of LRRK2. In this work, we investigate and identified significant regional differences in LRRK2 expression at the mRNA level, including a number of splicing events in the Ras of complex protein (Roc) and C-terminal of Roc domain (COR) of LRRK2, in the substantia nigra (SN) and occipital cortex (OCTX). Our findings indicate that the predominant form of LRRK2 mRNA is full length, with shorter isoforms present at a lower copy number. Our molecular modelling study suggests that splicing events in the ROC/COR domains will have major consequences on the enzymatic function and dimer formation of LRRK2. The implications of these are highly relevant to the broader effort to understand the biology and physiological functions of LRRK2, and to better characterize the role(s) of LRRK2 in the underlying mechanism leading to PD.

Details

Language :
English
ISSN :
14220067 and 19092784
Volume :
19
Issue :
9
Database :
Directory of Open Access Journals
Journal :
International Journal of Molecular Sciences
Publication Type :
Academic Journal
Accession number :
edsdoj.6288ab73eef844309a2b7fb5b90201c3
Document Type :
article
Full Text :
https://doi.org/10.3390/ijms19092784