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

International Journal of Molecular Sciences
Dimitrios VlachakisDaniah Trabzuni

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 ...Continue Reading

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Citations

Oct 6, 2020·Frontiers in Neuroscience·Hardy J RideoutJean-Marc Taymans
Aug 28, 2021·Biomolecules·Dominika Natalia Wojewska, Arjan Kortholt

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Methods Mentioned

BETA
electron microscopy
PCR
immunoprecipitation

Software Mentioned

Sequencer alignment
Ensembl
Molecular Operating Environment ( MOE )
MOE
Primer3 Alignment Search Tool BLAST

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