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Updated: May 22, 2026
Assaying the Kinase Activity of LRRK2 in vitro
Published on: January 18, 2012
High LRRK2 levels fail to induce or exacerbate neuronal alpha-synucleinopathy in mouse brain
Martin C Herzig1, Michael Bidinosti, Tatjana Schweizer
1Department of Neuroscience, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland.
Abstract:
The G2019S mutation in the multidomain protein leucine-rich repeat kinase 2 (LRRK2) is one of the most frequently identified genetic causes of Parkinson's disease (PD). Clinically, LRRK2(G2019S) carriers with PD and idiopathic PD patients have a very similar disease with brainstem and cortical Lewy pathology (α-synucleinopathy) as histopathological hallmarks. Some patients have Tau pathology. Enhanced kinase function of the LRRK2(G2019S) mutant protein is a prime suspect mechanism for carriers to develop PD but observations in LRRK2 knock-out, G2019S knock-in and kinase-dead mutant mice suggest that LRRK2 steady-state abundance of the protein also plays a determining role. One critical question concerning the molecular pathogenesis in LRRK2(G2019S) PD patients is whether α-synuclein (aSN) has a contributory role. To this end we generated mice with high expression of either wildtype or G2019S mutant LRRK2 in brainstem and cortical neurons. High levels of these LRRK2 variants left endogenous aSN and Tau levels unaltered and did not exacerbate or otherwise modify α-synucleinopathy in mice that co-expressed high levels of LRRK2 and aSN in brain neurons. On the contrary, in some lines high LRRK2 levels improved motor skills in the presence and absence of aSN-transgene-induced disease. Therefore, in many neurons high LRRK2 levels are well tolerated and not sufficient to drive or exacerbate neuronal α-synucleinopathy.
Insights
High levels of leucine-rich repeat kinase 2 (LRRK2) variants, including the Parkinson's disease-associated G2019S mutation, do not worsen alpha-synucleinopathy in mice. In fact, elevated LRRK2 levels can improve motor function, suggesting it is well-tolerated in neurons.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- The G2019S mutation in leucine-rich repeat kinase 2 (LRRK2) is a common genetic cause of Parkinson's disease (PD).
- LRRK2(G2019S) carriers and idiopathic PD patients share similar clinical and pathological features, including Lewy pathology (α-synucleinopathy).
- While enhanced LRRK2 kinase activity is implicated, the role of LRRK2 protein abundance in PD pathogenesis is also considered.
Purpose of the Study:
- To investigate the role of α-synuclein (aSN) in the molecular pathogenesis of LRRK2(G2019S) Parkinson's disease.
- To determine if high expression levels of wildtype or G2019S mutant LRRK2 influence α-synucleinopathy.
Main Methods:
- Generation of mouse models with high expression of wildtype or G2019S mutant LRRK2 in brainstem and cortical neurons.
- Assessment of endogenous α-synuclein and Tau levels.
- Evaluation of α-synucleinopathy in mice co-expressing high LRRK2 and α-synuclein.
Main Results:
- High LRRK2 levels did not alter endogenous α-synuclein or Tau levels.
- Elevated LRRK2 variants did not exacerbate α-synucleinopathy in mice co-expressing high LRRK2 and α-synuclein.
- In some lines, high LRRK2 levels improved motor skills, irrespective of α-synuclein transgene presence.
Conclusions:
- High LRRK2 levels are generally well-tolerated in neurons.
- Elevated LRRK2 abundance alone is insufficient to drive or worsen neuronal α-synucleinopathy.
- The role of α-synuclein in LRRK2(G2019S) PD pathogenesis requires further investigation beyond LRRK2 abundance.
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