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Int. J. Mol. Sci. 2018, 19(9), 2784; https://doi.org/10.3390/ijms19092784

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

1
Genetics Laboratory, Department of Biotechnology, Agricultural University of Athens, 75 Iera Odos Street, 11855 Athens, Greece
2
Laboratory of Enzyme Technology, Department of Biotechnology, School of Food, Biotechnology and Development, Agricultural University of Athens, 75 Iera Odos Street, 11855 Athens, Greece
3
Department of Informatics, Faculty of Natural and Mathematical Sciences, King’s College London, Strand, London WC2R 2LS, UK
4
Department of Neurodegenerative disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK
5
School of Pharmacy, University of Reading, Whiteknights, Reading RG6 6AP, UK
6
Division of Basic Neurosciences; Biomedical Research Foundation of the Academy of Athens, Soranou Efessiou 4, 11527 Athens, Greece
7
Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
*
Author to whom correspondence should be addressed.
Received: 14 August 2018 / Revised: 10 September 2018 / Accepted: 13 September 2018 / Published: 16 September 2018
(This article belongs to the Special Issue Genomics of Brain Disorders)
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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. View Full-Text
Keywords: LRRK2 mRNA expression; Human brain substantia nigra; Parkinson’s disease (PD); ROC/COR domain splicing events; WD40 domain in protein structure LRRK2 mRNA expression; Human brain substantia nigra; Parkinson’s disease (PD); ROC/COR domain splicing events; WD40 domain in protein structure
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Vlachakis, D.; Labrou, N.E.; Iliopoulos, C.; Hardy, J.; Lewis, P.A.; Rideout, H.; Trabzuni, D. Insights into the Influence of Specific Splicing Events on the Structural Organization of LRRK2. Int. J. Mol. Sci. 2018, 19, 2784.

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