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

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 LRR...

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Autores principales: Vlachakis, Dimitrios, Labrou, Nikolaos E., Iliopoulos, Costas, Hardy, John, Lewis, Patrick A., Rideout, Hardy, Trabzuni, Daniah
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6165039/
https://www.ncbi.nlm.nih.gov/pubmed/30223621
http://dx.doi.org/10.3390/ijms19092784
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author Vlachakis, Dimitrios
Labrou, Nikolaos E.
Iliopoulos, Costas
Hardy, John
Lewis, Patrick A.
Rideout, Hardy
Trabzuni, Daniah
author_facet Vlachakis, Dimitrios
Labrou, Nikolaos E.
Iliopoulos, Costas
Hardy, John
Lewis, Patrick A.
Rideout, Hardy
Trabzuni, Daniah
author_sort Vlachakis, Dimitrios
collection PubMed
description 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.
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spelling pubmed-61650392018-10-10 Insights into the Influence of Specific Splicing Events on the Structural Organization of LRRK2 Vlachakis, Dimitrios Labrou, Nikolaos E. Iliopoulos, Costas Hardy, John Lewis, Patrick A. Rideout, Hardy Trabzuni, Daniah Int J Mol Sci Communication 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. MDPI 2018-09-16 /pmc/articles/PMC6165039/ /pubmed/30223621 http://dx.doi.org/10.3390/ijms19092784 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Communication
Vlachakis, Dimitrios
Labrou, Nikolaos E.
Iliopoulos, Costas
Hardy, John
Lewis, Patrick A.
Rideout, Hardy
Trabzuni, Daniah
Insights into the Influence of Specific Splicing Events on the Structural Organization of LRRK2
title Insights into the Influence of Specific Splicing Events on the Structural Organization of LRRK2
title_full Insights into the Influence of Specific Splicing Events on the Structural Organization of LRRK2
title_fullStr Insights into the Influence of Specific Splicing Events on the Structural Organization of LRRK2
title_full_unstemmed Insights into the Influence of Specific Splicing Events on the Structural Organization of LRRK2
title_short Insights into the Influence of Specific Splicing Events on the Structural Organization of LRRK2
title_sort insights into the influence of specific splicing events on the structural organization of lrrk2
topic Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6165039/
https://www.ncbi.nlm.nih.gov/pubmed/30223621
http://dx.doi.org/10.3390/ijms19092784
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