Novel LRRK2 GTP-binding inhibitors reduced degeneration in Parkinson's disease cell and mouse models

Tianxia Li, Dejun Yang, Shijun Zhong, Joseph M. Thomas, Fengtian Xue, Jingnan Liu, Lingbo Kong, Pamela Voulalas, Hazem E. Hassan, Jae Sung Park, Alexander D. MacKerell, Wanli W. Smith

Research output: Contribution to journalArticle

Abstract

Mutations in the leucine-rich repeat kinase-2 (LRRK2) gene cause autosomal-dominant Parkinson's disease (PD) and contribute to sporadic PD. LRRK2 contains Guanosine-5'-triphosphate (GTP) binding, GTPase and kinase activities that have been implicated in the neuronal degeneration of PD pathogenesis, making LRRK2, a potential drug target. To date, there is no disease-modifying drug to slow the neuronal degeneration of PD and no published LRRK2 GTP domain inhibitor. Here, the biological functions of two novel GTP-binding inhibitors of LRRK2 were examined in PD cell and mouse models. Through a combination of computer-aided drug design (CADD) and LRRK2 bio-functional screens, two novel compounds, 68: and 70: , were shown to reduce LRRK2 GTP binding and to inhibit LRRK2 kinase activity in vitro and in cultured cell assays. Moreover, these two compounds attenuated neuronal degeneration in human SH-SY5Y neuroblastoma cells and mouse primary neurons expressing mutant LRRK2 variants. Although both compounds inhibited LRRK2 kinase activity and reduced neuronal degeneration, solubility problems with 70: prevented further testing in mice. Thus, only 68: was tested in a LRRK2-based lipopolysaccharide (LPS)-induced pre-inflammatory mouse model. 68: reduced LRRK2 GTP-binding activity and kinase activity in brains of LRRK2 transgenic mice after intraperitoneal injection. Moreover, LPS induced LRRK2 upregulation and microglia activation in mouse brains. These findings suggest that disruption of GTP binding to LRRK2 represents a potential novel therapeutic approach for PD intervention and that these novel GTP-binding inhibitors provide both tools and lead compounds for future drug development.

Original languageEnglish (US)
Pages (from-to)6212-6222
Number of pages11
JournalHuman molecular genetics
Volume23
Issue number23
DOIs
StatePublished - Dec 1 2014
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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  • Cite this

    Li, T., Yang, D., Zhong, S., Thomas, J. M., Xue, F., Liu, J., Kong, L., Voulalas, P., Hassan, H. E., Park, J. S., MacKerell, A. D., & Smith, W. W. (2014). Novel LRRK2 GTP-binding inhibitors reduced degeneration in Parkinson's disease cell and mouse models. Human molecular genetics, 23(23), 6212-6222. https://doi.org/10.1093/hmg/ddu341