Impaired dopaminergic neurotransmission and microtubule-associated protein tau alterations in human LRRK2 transgenic mice
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Metabolic Labeling of Leucine Rich Repeat Kinases 1 and 2 with Radioactive Phosphate
Published on: September 18, 2013
H L Melrose1, J C Dächsel, B Behrouz
1Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA. Melrose.heather@mayo.edu
Abstract:
Mutations in the Leucine Rich Repeat Kinase 2 (LRRK2) gene, first described in 2004 have now emerged as the most important genetic finding in both autosomal dominant and sporadic Parkinson's disease (PD). While a formidable research effort has ensued since the initial gene discovery, little is known of either the normal or the pathological role of LRRK2. We have created lines of mice that express human wild-type (hWT) or G2019S Lrrk2 via bacterial artificial chromosome (BAC) transgenesis. In vivo analysis of the dopaminergic system revealed abnormal dopamine neurotransmission in both hWT and G2019S transgenic mice evidenced by a decrease in extra-cellular dopamine levels, which was detected without pharmacological manipulation. Immunopathological analysis revealed changes in localization and increased phosphorylation of microtubule binding protein tau in G2019S mice. Quantitative biochemical analysis confirmed the presence of differential phospho-tau species in G2019S mice but surprisingly, upon dephosphorylation the tau isoform banding pattern in G2019S mice remained altered. This suggests that other post-translational modifications of tau occur in G2019S mice. We hypothesize that Lrrk2 may impact on tau processing which subsequently leads to increased phosphorylation. Our models will be useful for further understanding of the mechanistic actions of LRRK2 and future therapeutic screening.
Insights
Mutations in Leucine Rich Repeat Kinase 2 (LRRK2) are key to Parkinson's disease (PD). LRRK2 may impact tau processing, leading to increased phosphorylation and altered dopamine neurotransmission in PD.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Mutations in Leucine Rich Repeat Kinase 2 (LRRK2) are the most significant genetic factor in Parkinson's disease (PD).
- The precise role of LRRK2 in normal brain function and in the pathology of PD remains largely unknown.
- Understanding LRRK2's function is crucial for developing effective PD therapies.
Purpose of the Study:
- To investigate the in vivo effects of expressing human wild-type (hWT) and G2019S Lrrk2 in mice.
- To analyze the impact of Lrrk2 expression on the dopaminergic system and tau protein.
- To establish novel mouse models for studying LRRK2 mechanisms and screening therapeutic interventions.
Main Methods:
- Generation of transgenic mouse lines expressing hWT or G2019S Lrrk2 using bacterial artificial chromosome (BAC) transgenesis.
- In vivo analysis of the dopaminergic system, including extracellular dopamine level measurements.
- Immunopathological and quantitative biochemical analyses of tau protein phosphorylation and post-translational modifications.
Main Results:
- Transgenic mice expressing both hWT and G2019S Lrrk2 exhibited abnormal dopamine neurotransmission, indicated by decreased extracellular dopamine levels.
- G2019S Lrrk2 mice showed altered tau protein localization and increased phosphorylation.
- Biochemical analysis revealed differential phospho-tau species in G2019S mice, with persistent alterations even after dephosphorylation, suggesting other modifications.
Conclusions:
- LRRK2, particularly the G2019S mutation, influences tau processing and phosphorylation, potentially contributing to Parkinson's disease pathology.
- The developed mouse models provide valuable tools for elucidating LRRK2's mechanistic actions in PD.
- These models will facilitate future therapeutic screening for LRRK2-related Parkinson's disease.
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