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Functional and behavioral consequences of Parkinson's disease-associated LRRK2-G2019S mutation
Deanna L Benson1, Bridget A Matikainen-Ankney2, Ayan Hussein2
1Department of Neuroscience, Friedman Brain Institute, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY 10029, U.S.A. deanna.benson@mssm.edu.
Abstract:
LRRK2 mutation is the most common inherited, autosomal dominant cause of Parkinson's disease (PD) and has also been observed in sporadic cases. Most mutations result in increased LRRK2 kinase activity. LRRK2 is highly expressed in brain regions that receive dense, convergent innervation by dopaminergic and glutamatergic axons, and its levels rise developmentally coincident with glutamatergic synapse formation. The onset and timing of expression suggests strongly that LRRK2 regulates the development, maturation and function of synapses. Several lines of data in mice show that LRRK2-G2019S, the most common LRRK2 mutation, produces an abnormal gain of pathological function that affects synaptic activity, spine morphology, persistent forms of synapse plasticity and behavioral responses to social stress. Effects of the mutation can be detected as early as the second week of postnatal development and can last or have consequences that extend into adulthood and occur in the absence of dopamine loss. These data suggest that the generation of neural circuits that support complex behaviors is modified by LRRK2-G2019S. Whether such alterations impart vulnerability to neurons directly or indirectly, they bring to the forefront the idea that neural circuits within which dopamine neurons eventually degenerate are assembled and utilized in ways that are distinct from circuits that lack this mutation and may contribute to non-motor symptoms observed in humans with PD.
Insights
Parkinson's disease (PD) linked LRRK2 mutations impact neural circuit development and function, affecting synaptic activity and behavior even before dopamine neuron loss. This suggests LRRK2 plays a key role in assembling brain circuits vulnerable to PD.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common cause of inherited Parkinson's disease (PD).
- Increased LRRK2 kinase activity is a common outcome of these mutations.
- LRRK2 is expressed in brain regions crucial for dopaminergic and glutamatergic signaling and its expression coincides with synapse development.
Purpose of the Study:
- To investigate the role of LRRK2 in synaptic development, maturation, and function.
- To examine the effects of the common LRRK2-G2019S mutation on synaptic activity and neural circuits.
- To understand how LRRK2 mutations may contribute to Parkinson's disease pathogenesis and non-motor symptoms.
Main Methods:
- Utilized mouse models carrying the LRRK2-G2019S mutation.
- Assessed synaptic activity, spine morphology, and synapse plasticity.
- Evaluated behavioral responses, including social stress.
- Examined effects from early postnatal development into adulthood.
Main Results:
- The LRRK2-G2019S mutation leads to abnormal gain of function affecting synaptic activity and spine morphology.
- Altered synaptic plasticity and behavioral responses to social stress were observed.
- These effects are detectable early in development and persist into adulthood, even without dopamine loss.
- Neural circuit assembly and utilization are modified by the LRRK2-G2019S mutation.
Conclusions:
- LRRK2 regulates the development, maturation, and function of synapses.
- The LRRK2-G2019S mutation alters neural circuit formation, potentially contributing to PD vulnerability.
- Distinct neural circuit assembly in individuals with LRRK2 mutations may underlie non-motor symptoms in Parkinson's disease.