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Assaying the Kinase Activity of LRRK2 in vitro
Published on: January 18, 2012
Mutant LRRK2 enhances glutamatergic synapse activity and evokes excitotoxic dendrite degeneration
Edward D Plowey1, Jon W Johnson2, Erin Steer3
1Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA; Department of Pathology, Stanford University, Stanford, CA, USA.
Abstract:
Mutations in leucine-rich repeat kinase 2 (LRRK2), which are associated with autosomal dominant Parkinson's disease, elicit progressive dendrite degeneration in neurons. We hypothesized that synaptic dysregulation contributes to mutant LRRK2-induced dendritic injury. We performed in vitro whole-cell voltage clamp studies of glutamatergic receptor agonist responses and glutamatergic synaptic activity in cultured rat cortical neurons expressing full-length wild-type and mutant forms of LRRK2. Expression of the pathogenic G2019S or R1441C LRRK2 mutants resulted in larger whole-cell current responses to direct application of AMPA and NMDA receptor agonists. In addition, mutant LRRK2-expressing neurons exhibited an increased frequency of spontaneous miniature excitatory postsynaptic currents (mEPSCs) in conjunction with increased excitatory synapse density as assessed by immunofluorescence for PSD95 and VGLUT1. Mutant LRRK2-expressing neurons showed enhanced vulnerability to acute synaptic glutamate stress. Furthermore, treatment with the NMDA receptor antagonist memantine significantly protected against subsequent losses in dendrite length and branching complexity. These data demonstrate an early association between mutant LRRK2 and increased excitatory synapse activity, implicating an excitotoxic contribution to mutant LRRK2 induced dendrite degeneration.
Insights
Mutations in leucine-rich repeat kinase 2 (LRRK2) cause Parkinson's disease by increasing excitatory synapse activity, leading to dendrite degeneration. Memantine treatment protected neurons, suggesting excitotoxicity contributes to this damage.
Area of Science:
- Neuroscience
- Cell Biology
- Genetics
Background:
- Mutations in leucine-rich repeat kinase 2 (LRRK2) are a common cause of autosomal dominant Parkinson's disease.
- LRRK2 mutations lead to progressive dendrite degeneration in neurons.
Purpose of the Study:
- To investigate the role of synaptic dysregulation in mutant LRRK2-induced dendritic injury.
- To determine if increased excitatory synaptic activity contributes to neurodegeneration in Parkinson's disease models.
Main Methods:
- In vitro whole-cell voltage clamp studies were performed on cultured rat cortical neurons.
- Neurons expressed wild-type or mutant LRRK2 (G2019S, R1441C).
- Responses to glutamatergic receptor agonists and synaptic activity were measured; synapse density was assessed via immunofluorescence.
Main Results:
- Mutant LRRK2 expression increased neuronal responses to AMPA and NMDA receptor agonists.
- Increased frequency of spontaneous miniature excitatory postsynaptic currents (mEPSCs) and higher excitatory synapse density were observed.
- Mutant LRRK2 neurons exhibited heightened vulnerability to glutamate stress, but memantine treatment conferred protection.
Conclusions:
- Mutant LRRK2 is associated with early increases in excitatory synapse activity.
- Excitotoxicity likely contributes to dendrite degeneration in LRRK2-related Parkinson's disease.
- Targeting excitotoxicity may offer a therapeutic strategy for LRRK2 Parkinson's disease.
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