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Published on: March 7, 2019
Lrrk2 localization in the primate basal ganglia and thalamus: a light and electron microscopic analysis in monkeys
1Yerkes National Primate Research Center, Emory University, Atlanta, GA 30322, USA.
Abstract:
The Leucine Rich Repeat Kinase-2 (LRRK2) gene is a common mutation target in Parkinson's disease (PD), but the cellular mechanisms by which such mutations underlie the pathophysiology of PD remain poorly understood. Thus, to better characterize the neuronal target sites of LRRK2 mutations in the primate brain, we studied the cellular and ultrastructural localization of Lrrk2 immunoreactivity in the monkey basal ganglia. As previously described, the monkey striatum was the most enriched basal ganglia structure in Lrrk2 labeling. Both projection neurons and parvalbumin-containing GABAergic interneurons displayed Lrrk2 immunoreactivity. At the electron microscopic level, striatal Lrrk2 labeling was associated predominantly with dendritic shafts and subsets of putative glutamatergic axon terminals. At the pallidal level, moderate cellular Lrrk2 immunostaining was found in the external globus pallidus (GPe), while neurons in the internal globus pallidus (GPi) were devoid of Lrrk2 immunoreactivity. Strong labeling was associated with cholinergic neurons in the nucleus basalis of Meynert. Midbrain dopaminergic neurons in the primate substantia nigra pars compacta (SNc) and ventral tegmental area harbored a significant level of Lrrk2 labeling, while neurons in the subthalamic nucleus were lightly immunostained. Most thalamic nuclei were enriched in Lrrk2 immunoreactivity, except for the centromedian nucleus that was completely devoid of labeling. Thus, Lrrk2 protein is widely distributed in the monkey basal ganglia, suggesting that gene mutations in PD may result in multifarious pathophysiological effects that could impact various target sites in the functional circuitry of the primate basal ganglia.
Insights
Leucine Rich Repeat Kinase-2 (LRRK2) protein is widely distributed in the monkey basal ganglia, impacting various neuronal types. Understanding LRRK2 localization is crucial for Parkinson's disease (PD) research.
Area of Science:
- Neuroscience
- Cell Biology
- Genetics
Background:
- Leucine Rich Repeat Kinase-2 (LRRK2) gene mutations are common in Parkinson's disease (PD).
- The precise cellular mechanisms linking LRRK2 mutations to PD pathophysiology are not fully understood.
- Investigating LRRK2's localization in the primate brain can elucidate its role in PD.
Purpose of the Study:
- To determine the cellular and ultrastructural localization of Lrrk2 immunoreactivity in the monkey basal ganglia.
- To identify specific neuronal populations and subcellular compartments expressing Lrrk2.
- To provide insights into the potential impact of LRRK2 mutations on basal ganglia circuitry.
Main Methods:
- Immunohistochemistry and immunoelectron microscopy were used to detect Lrrk2 protein.
- The study focused on various regions of the monkey basal ganglia, including the striatum, globus pallidus, substantia nigra, and thalamus.
Main Results:
- Lrrk2 immunoreactivity was widespread in the monkey basal ganglia, notably in the striatum, nucleus basalis of Meynert, midbrain dopaminergic neurons (SNc, VTA), and most thalamic nuclei.
- Projection neurons and parvalbumin interneurons in the striatum showed Lrrk2 labeling, associated with dendrites and axon terminals.
- The external globus pallidus (GPe) exhibited moderate Lrrk2 staining, while the internal globus pallidus (GPi) and centromedian thalamic nucleus were devoid of it.
Conclusions:
- Lrrk2 protein is broadly distributed across diverse neuronal types and regions within the primate basal ganglia.
- The widespread presence of Lrrk2 suggests that PD-associated mutations could exert multifarious pathophysiological effects.
- Understanding LRRK2's localization is key to deciphering its role in the complex functional circuitry affected in Parkinson's disease.
