Regulation of LRRK2 promoter activity and gene expression by Sp1

Abstract

BackgroundThe dopaminergic neurodegeneration in the nigrostriatal pathway is a prominent neuropathological feature of Parkinson’s disease (PD). Mutations in various genes have been linked to familial PD, and leucine-rich repeat kinase 2 (LRRK2) gene is one of them. LRRK2 is a large complex protein, belonging to the ROCO family of proteins. Recent studies suggest that the level of LRRK2 protein is one of the contributing factors to PD pathogenesis. However, it remains elusive how LRRK2 is regulated at the transcriptional and translational level.ResultsIn this study, we cloned a 1738 bp 5’-flanking region of the human LRRK2 gene. The transcriptional start site (TSS) was located to 135 bp upstream of translational start site and the fragment −118 to +133 bp had the minimum promoter activity required for transcription. There were two functional Sp1- responsive elements on the human LRRK2 gene promoter revealed by electrophoretic mobility shift assay (EMSA). Sp1 overexpression promoted LRRK2 transcription and translation in the cellular model. On the contrary, application of mithramycin A inhibited LRRK2 transcriptional and translational activities.ConclusionThis is the first study indicating that Sp1 signaling plays an important role in the regulation of human LRRK2 gene expression. It suggests that controlling LRRK2 level by manipulating Sp1 signaling may be beneficial to attenuate PD-related neuropathology.

VIP Induces Changes in the F-/G-Actin Ratio of Schlemm's Canal Endothelium via LRRK2 Transcriptional Regulation

“…A previous study identified potential transcription factors of LRRK2 and noted that Sp1 can regulate the promoter activity and gene expression of LRRK2. 40 The mRNA and protein expression levels of Sp1 showed the same trend as the expression levels of LRRK2 in this study; VIP (1, 10, or 50 μM) promoted the mRNA and protein expression levels of Sp1 in HUVECs (Figs. 5A, 5D).…”

“…According to the transcription factor binding sites of the LRRK2 gene, a previous study identified several putative transcription factors for LRRK2, including Sp1, GATA1/2, AP-1, HNF-3α, and NF-AT1. 40 In this study, we evaluated the changes in RNA expression after the application of VIP to HUVECs and found that Sp1 showed the most significant positive changes, indicating that VIP can positively regulate the RNA expression of Sp1. In addition, a previous study also confirmed that Sp1 is able to regulate the promoter activity and gene expression of LRRK2.…”

“…This study result is also consistent with a previous study that indicated that Sp1 signaling is important for the regulation of LRRK2 gene expression. 40 Sp1 is a classic transcription factor involved in various molecular pathways and can bind to GC-boxes and GT/CACC-boxes. Its binding sequence is (G/T)GGGCGG(G/A)(G/A)(C/T), 35,36 which also appears in the LRRK2 promoter; thus, Sp1 can bind to the LRRK2 promotor and upregulate the expression of LRRK2.…”

“…Its binding sequence is (G/T)GGGCGG(G/A)(G/A)(C/T), 35,36 which also appears in the LRRK2 promoter; thus, Sp1 can bind to the LRRK2 promotor and upregulate the expression of LRRK2. 40 A major limitation of this study was that we performed experiments on HUVECs rather than primary SC cells. It is not clear whether our HUVEC experiment results could also be observed in primary SC cells; thus, further studies on primary SC cells would be necessary.…”

MiR‐29c protects against inflammation and apoptosis in Parkinson's disease model in vivo and in vitro by targeting SP1

“…Some research had discovered that the expression of SP1 was increased in the brains of patients or models with AD, PD or other neurodegenerative disorders . A prior study also noted that SP1 signalling was significant in ameliorating the neuropathological changes involving PD by the manipulation of LRRK2 . In addition, some studies also demonstrated that SP1 participated in modulating inflammatory response in diverse diseases .…”