Pathogenic LRRK2 Mutations Do Not Alter Gene Expression in Cell Model Systems or Human Brain Tissue

Abstract

Point mutations in LRRK2 cause autosomal dominant Parkinson's disease. Despite extensive efforts to determine the mechanism of cell death in patients with LRRK2 mutations, the aetiology of LRRK2 PD is not well understood. To examine possible alterations in gene expression linked to the presence of LRRK2 mutations, we carried out a case versus control analysis of global gene expression in three systems: fibroblasts isolated from LRRK2 mutation carriers and healthy, non-mutation carrying controls; brain tissue from G2019S mutation carriers and controls; and HEK293 inducible LRRK2 wild type and mutant cell lines. No significant alteration in gene expression was found in these systems following correction for multiple testing. These data suggest that any alterations in basal gene expression in fibroblasts or cell lines containing mutations in LRRK2 are likely to be quantitatively small. This work suggests that LRRK2 is unlikely to play a direct role in modulation of gene expression, although it remains possible that this protein can influence mRNA expression under pathogenic cicumstances.

Orchestrated increase of dopamine and PARK mRNAs but not miR-133b in dopamine neurons in Parkinson's disease

“…These findings indicate a concerted regulation of these PARK-genes in SN DA neurons in PD, as a protective response to increased proteasomal and lysosomal and/or autophagosomal demands. The finding that LRRK2 (PARK8) mRNA levels were not altered in remaining DA neurons from PD brains is in accordance with a study showing that pathogenic LRRK2 mutations do not alter gene expression in human brain tissue (Devine et al., 2011a). Increased expression of wild-type LRRK2 accelerates alpha-synuclein-induced neurodegeneration and is thus not expected as an allostatic survival mechanism of SN DA neurons in PD (Caguci, 2003; Lin et al., 2009).…”

The LRRK2 signalling system

“…It was found that transcription activity was upregulated in G2019S mice compared to knockout and wild-type when each LRRK2 condition was overexpressed. This suggests that LRRK2 has some function or influence on the transcription process (Nikonova et al 2012), although again the data on this are conflicting (Devine et al 2011). …”

Studying neurodegenerative diseases in culture models

“…13 Recently, it could be demonstrated that overexpression of leucine-rich repeat kinase 2 (LRRK2) does not result in altered gene expression in HEK293 cells. 15 Mutations in LRRK2 are strongly associated with late-onset autosomal dominant PD, and HEK293 may be suitable to go for candidate pharmacological screening for LRRK2 inhibitors. 16 Moreover, mechanisms of possible in vitro transfer of aSyn and its modified species may be studied in this cell line.…”