Exp Neurobiol.  2021 Jun;30(3):232-243. 10.5607/en21003.

Ciliogenesis is Not Directly Regulated by LRRK2 Kinase Activity in Neurons

Affiliations
  • 1InAm Neuroscience Research Center, Sanbon Medical Center, College of Medicine, Wonkwang University, Gunpo 15865, Korea
  • 2Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea
  • 3Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology, Daejeon 34141, Korea
  • 4Paik Institute for Clinical Research, Inje University College of Medicine, Busan 47392, Korea
  • 5College of Pharmacy, CHA University, Seongnam 13496, Korea
  • 6Division of Clinical Medicine, Korea Institute of Oriental Medicine, Daejeon 34054, Korea
  • 7Division of Herbal Medicine Research, Korea Institute of Oriental Medicine, Daejeon 34054, Korea
  • 8Department of Convergence Biomedical Science, Inje University College of Medicine, Busan 47392, Korea
  • 9Department of Neurology, Sanbon Medical Center, College of Medicine, Wonkwang University, Gunpo 15865, Korea

Abstract

Mutations in the Leucine-rich repeat kinase 2 (LRRK2 ) gene are the most prevalent cause of familial Parkinson’s disease (PD). The increase in LRRK2 kinase activity observed in the pathogenic G2019S mutation is important for PD development. Several studies have reported that increased LRRK2 kinase activity and treatment with LRRK2 kinase inhibitors decreased and increased ciliogenesis, respectively, in mouse embryonic fibroblasts (MEFs) and retinal pigment epithelium (RPE) cells. In contrast, treatment of SH-SY5Y dopaminergic neuronal cells with PD-causing chemicals increased ciliogenesis. Because these reports were somewhat contradictory, we tested the effect of LRRK2 kinase activity on ciliogenesis in neurons. In SH-SY5Y cells, LRRK2 inhibitor treatment slightly increased ciliogenesis, but serum starvation showed no increase. In rat primary neurons, LRRK2 inhibitor treatment repeatedly showed no significant change. Little difference was observed between primary cortical neurons prepared from wild-type (WT) and G2019S +/- mice. However, a significant increase in ciliogenesis was observed in G2019S +/- compared to WT human fibroblasts, and this pattern was maintained in neural stem cells (NSCs) differentiated from the induced pluripotent stem cells (iPSCs) prepared from the same WT/G2019S fibroblast pair. NSCs differentiated from G2019S and its gene-corrected WT counterpart iPSCs were also used to test ciliogenesis in an isogenic background. The results showed no significant difference between WT and G2019S regardless of kinase inhibitor treatment and B27-deprivation-mimicking serum starvation. These results suggest that LRRK2 kinase activity may be not a direct regulator of ciliogenesis and ciliogenesis varies depending upon the cell type or genetic background.

Keyword

Primary cilia; Neuron; LRRK2 kinase; Ciliogenesis; Parkinson’s disease
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