Related Experiment Video
Updated: Apr 19, 2026
Rab10 Phosphorylation Detection by LRRK2 Activity Using SDS-PAGE with a Phosphate-binding Tag
Published on: December 14, 2017
Abberant protein synthesis in G2019S LRRK2 Drosophila Parkinson disease-related phenotypes
Ian Martin1, Leire Abalde-Atristain, Jungwoo Wren Kim
1a Neuroregeneration and Stem Cell Programs; Institute for Cell Engineering; Johns Hopkins University School of Medicine ; Baltimore , MD USA.
Abstract:
LRRK2 mutations are a frequent cause of familial Parkinson disease (PD) and are also found in a number of sporadic PD cases. PD-linked G2019S and I2020T mutations in the kinase domain of LRRK2 result in elevated kinase activity, which is required for the toxicity of these pathogenic variants in cell and animal models of PD. We recently reported that LRRK2 interacts with and phosphorylates a number of mammalian ribosomal proteins, several of which exhibit increased phosphorylation via both G2019S and I2020T LRRK2. Blocking the phosphorylation of ribosomal protein s15 through expression of phospho-deficient T136A s15 prevents age-associated locomotor deficits and dopamine neuron loss caused by G2019S LRRK2 expression in Drosophila indicating that s15 is a pathogenic LRRK2 substrate. We previously described that G2019S LRRK2 causes an induction of bulk mRNA translation that is blocked by T136A s15 or the protein synthesis inhibitor anisomycin. Here, we report the protective effects of the eIF4E/eIF4G interaction inhibitor 4EGI-1, in preventing neurodegenerative phenotypes in G2019S LRRK2 flies, and discuss how our findings and those of other groups provide a framework to begin investigating the mechanistic impact of LRRK2 on translation.
Insights
Parkinson disease (PD) linked LRRK2 mutations increase ribosomal protein S15 phosphorylation, driving neurodegeneration. Inhibiting this pathway with 4EGI-1 protects against PD-related phenotypes in flies.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Mutations in Leucine-Rich Repeat Kinase 2 (LRRK2) are a significant cause of familial and sporadic Parkinson disease (PD).
- Pathogenic LRRK2 variants, such as G2019S and I2020T, exhibit increased kinase activity and are implicated in PD pathogenesis.
- LRRK2 has been shown to interact with and phosphorylate ribosomal proteins, suggesting a role in protein synthesis regulation.
Purpose of the Study:
- To investigate the role of LRRK2-mediated ribosomal protein phosphorylation in Parkinson disease.
- To determine if blocking ribosomal protein S15 phosphorylation can prevent neurodegenerative phenotypes associated with LRRK2 mutations.
- To explore the therapeutic potential of inhibiting the LRRK2-translation pathway.
Main Methods:
- Utilized Drosophila melanogaster models expressing G2019S LRRK2 to study neurodegenerative phenotypes.
- Investigated the phosphorylation status of ribosomal protein S15 in response to LRRK2 mutations.
- Assessed the impact of a phospho-deficient S15 mutant (T136A) on locomotor deficits and dopamine neuron loss.
- Examined the effects of the eIF4E/eIF4G interaction inhibitor 4EGI-1 on G2019S LRRK2-induced phenotypes.
Main Results:
- LRRK2 mutations (G2019S, I2020T) lead to increased phosphorylation of ribosomal protein S15.
- Expression of phospho-deficient T136A S15 prevents age-associated locomotor deficits and dopamine neuron loss in G2019S LRRK2 flies.
- G2019S LRRK2 induces bulk mRNA translation, which is blocked by T136A S15 or anisomycin.
- The eIF4E/eIF4G interaction inhibitor 4EGI-1 demonstrates protective effects against neurodegenerative phenotypes in G2019S LRRK2 flies.
Conclusions:
- Ribosomal protein S15 is a pathogenic substrate of LRRK2 in Parkinson disease.
- Targeting LRRK2-mediated translation offers a potential therapeutic strategy for Parkinson disease.
- These findings provide a framework for understanding the mechanistic link between LRRK2 and translation in neurodegeneration.
Related Concept Videos
01:24Parkinson Disease ll: Pathophysiology
01:24Parkinson Disease l: Introduction