Abstract
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most frequent cause of autosomal dominant Parkinson’s disease (PD), producing psychiatric and motor symptoms. We conducted this study to explore whether microglial dopaminergic (DAergic) fiber refinement and synaptic pruning are involved in the abnormal behavioral phenotypes of carriers of the LRRK2 G2019S mutation, by employing young and middle-aged PD model mice. The results revealed a characteristic late-onset hyperactivity and a progressive decline in the motor coordination of the LRRK2 G2019S mutation mice. LRRK2 G2019S mutation-induced aberrant microglial morphogenesis, with more branches and junctions per cell, resulted in excessive microglial refinement of dopaminergic (DAergic) fibers. Moreover, aberrant synaptic pruning distinctly impacted the prefrontal cortex (PFC) and dorsal striatum (DS), with significantly higher spine density in the PFC but the opposite effects in the DS region. Furthermore, LRRK2 G2019S mutation remodeled the inflammatory transcription landscape of microglia, rendering certain cerebral areas highly susceptible to microglial immune response. These findings indicate that LRRK2 G2019S mutation induces the production of inflammatory cytokines and mediates abnormal microglial morphogenesis and activity, resulting in abnormal phagocytosis, synaptic pruning and loss of DAergic fibers during aging, and, eventually, PD-related behavioral abnormalities.
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The datasets used and/or analyzed in this study are available from the corresponding authors on reasonable request.
Abbreviations
- PD:
-
Parkinson’s disease
- LRRK2:
-
Leucine-rich repeat kinase 2
- DA:
-
Dopaminergic
- DAT:
-
Dopamine transporter
- TH:
-
Tyrosine hydroxylase
- CD68:
-
Cluster of differentiation 68
- DS:
-
Dorsal striatum
- GS:
-
LRRK2 G2019S mutation mice
- Iba1:
-
Ionized calcium binding adaptor molecule 1
- PFC:
-
Prefrontal cortex
- PSD95:
-
Postsynaptic density protein 95
- VGLUT1:
-
Vesicular glutamate transporter 1
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Acknowledgements
We would like to thank Professor Hongzhi Huang from School of Arts and Sciences of Fujian Medical University for his kind proofreading and polishing of this manuscript.
Funding
This work was supported by grants from the National Natural Science Foundation of China (No. 81771179, No. 82071175); Natural Science Foundation (Key Project) of Fujian Province, China (No. 2020J02022); Fujian Provincial Health-Education Joint Research Project (No. WKJ2016-2–08); Startup Fund for scientific research from Fujian Medical University (No. 2017XQ2023, No. 2017XQ2035).
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Xiaodong Pan conceived the study design and Qiuyang Zhang conducted the animal study and quantitative analysis, and they were chief contributors in writing the manuscript. Xiaojuan Cheng, Wei Wu, Siyu Yang and Hanlin You performed the animal behavior study and histochemical experiments. Xiaochun Chen, Nan Liu and Zucheng Ye reviewed the manuscript. All authors read and approved the final manuscript.
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All animal experimental procedures conformed to the National Institute of Health Guidelines for the Care and Use of Laboratory Animals and were approved by the Institutional Animal Care and Use Committee of Fujian Medical University.
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Zhang, Q., Cheng, X., Wu, W. et al. Age-related LRRK2 G2019S Mutation Impacts Microglial Dopaminergic Fiber Refinement and Synaptic Pruning Involved in Abnormal Behaviors. J Mol Neurosci 72, 527–543 (2022). https://doi.org/10.1007/s12031-021-01896-6
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DOI: https://doi.org/10.1007/s12031-021-01896-6