Related Experiment Video
Updated: Oct 13, 2025
Metabolic Labeling of Leucine Rich Repeat Kinases 1 and 2 with Radioactive Phosphate
Published on: September 18, 2013
Dysregulated mRNA Translation in the G2019S LRRK2 and LRRK2 Knock-Out Mouse Brains
Jungwoo Wren Kim1,2,3, Xiling Yin1,4, Ian Martin1,4
1Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
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.
Insights
The G2019S mutation in leucine-rich repeat kinase 2 (LRRK2) affects mRNA translation in the brain, leading to calcium dysregulation. This study confirms LRRK2
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- The G2019S mutation in leucine-rich repeat kinase 2 (LRRK2) is a known cause of familial Parkinson's disease (PD).
- Previous research indicated G2019S LRRK2 impacts mRNA translation, particularly for transcripts with complex 5' untranslated regions (UTRs).
- This effect was observed in Drosophila and human stem cell models, linked to calcium channel expression and homeostasis disruption.
Purpose of the Study:
- To investigate the role of LRRK2 kinase activity in mRNA translation regulation in vivo.
- To determine if the G2019S mutation-associated translational dysregulation occurs in mammalian brains.
- To examine the impact of LRRK2 on translation of mRNAs with complex 5' UTRs and subsequent calcium homeostasis.
Main Methods:
- Ribosome profiling in mouse brains expressing G2019S LRRK2 and in LRRK2 knock-out (KO) mice.
- Reporter assays to assess 5' UTR-mediated translation.
- Analysis of calcium influx in substantia nigra pars compacta (SNpc) dopamine neurons.
Main Results:
- mRNAs with complex 5' UTR secondary structures were preferentially translated in G2019S LRRK2-expressing mouse brains.
- This 5' UTR preference was independent of translation initiation factors.
- Translation of these specific mRNAs was downregulated in LRRK2 KO mouse brains, highlighting LRRK2's role in their regulation.
- Increased calcium influx was observed in SNpc dopamine neurons of G2019S LRRK2 mice.
Conclusions:
- LRRK2 plays a critical role in regulating mRNA translation in the mammalian brain.
- The G2019S mutation in LRRK2 leads to translational defects.
- These defects contribute to calcium dysregulation, potentially underlying Parkinson's disease pathogenesis.
