Dysregulated mRNA Translation in the G2019S LRRK2 and LRRK2 Knock-Out Mouse Brains

Abstract

The G2019S mutation in leucine-rich repeat kinase 2 (LRRK2) causes familial Parkinson’s disease (PD) and is also found in a subset of idiopathic cases. Prior studies in Drosophila and human induced pluripotent stem cell (iPSC)-derived dopamine neurons uncovered a pronounced effect of G2019S LRRK2 on mRNA translation. It was previously reported that G2019S LRRK2 promotes translation of mRNAs with complex 5′ untranslated region (UTR) secondary structure, resulting in increased expression of calcium channels and dysregulated calcium homeostasis in human dopamine neurons. Here, we show that dysregulated translation occurs in the brains of mammalian LRRK2 models in vivo. Through ribosome profiling studies of global translation, we observe that mRNAs with complex 5′UTR structure are also preferentially translated in the G2019S LRRK2-expressing mouse brain. Reporter assays suggest that this 5′UTR preference is independent of translation initiation factors. Conversely, translation of mRNAs with complex 5′UTR secondary structure is downregulated in LRRK2 knock-out (KO) mouse brain, indicating a robust link between LRRK2 kinase activity and translation of mRNA with complex 5′UTR structure. Further, substantia nigra pars compacta (SNpc) dopamine neurons in the G2019S LRRK2-expressing brain exhibit increased calcium influx, which is consistent with the previous report from human dopamine neurons. These results collectively suggest that LRRK2 plays a mechanistic role in translational regulation, and the G2019S mutation in LRRK2 causes translational defects leading to calcium dysregulation in the mammalian brain.

Significance Statement

Parkinson’s disease (PD)-linked G2019S mutation of leucine-rich repeat kinase 2 (LRRK2) is known to cause abnormalities in mRNA translation. These translational defects were suggested to cause calcium dysregulation, thereby imposing a long-term cellular stress to dopamine neurons. While these effects of G2019S LRRK2 on mRNA translation have been seen in Drosophila brain tissues and cultured mammalian neurons, translational profiling of the mammalian brain expressing G2019S LRRK2 has not been reported. In this study, we employed ribosome profiling to survey mRNA translation in the brains of LRRK2 mouse models, thereby demonstrating that the G2019S LRRK2 mutation broadly alters mRNA translation in the mouse brain.