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Age-related LRRK2 G2019S Mutation Impacts Microglial Dopaminergic Fiber Refinement and Synaptic Pruning Involved in

Qiuyang Zhang1,2,3,4, Xiaojuan Cheng1,2,3,4, Wei Wu5

  • 1Department of Neurology, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, 350001, China.

Journal of Molecular Neuroscience : MN
|August 19, 2021
PubMed

Insights

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause Parkinson's disease (PD). This study shows LRRK2 G2019S mutation causes abnormal microglial activity, leading to synaptic pruning and DAergic fiber loss, ultimately causing PD behaviors.

Area of Science:

  • Neuroscience
  • Genetics
  • Cell Biology

Background:

  • Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are a primary genetic cause of autosomal dominant Parkinson's disease (PD).
  • LRRK2 mutations lead to both psychiatric and motor symptoms characteristic of PD.

Purpose of the Study:

  • To investigate the role of microglial dopaminergic (DAergic) fiber refinement and synaptic pruning in the abnormal behavioral phenotypes associated with the LRRK2 G2019S mutation.
  • To explore the impact of the LRRK2 G2019S mutation on microglial function and its contribution to PD pathogenesis.

Main Methods:

  • Utilized young and middle-aged Parkinson's disease model mice carrying the LRRK2 G2019S mutation.
  • Analyzed microglial morphology, dopaminergic fiber refinement, synaptic pruning in the prefrontal cortex (PFC) and dorsal striatum (DS), and the inflammatory transcriptional landscape of microglia.

Main Results:

  • LRRK2 G2019S mutation mice exhibited late-onset hyperactivity and progressive motor coordination decline.
  • Aberrant microglial morphogenesis led to excessive refinement of DAergic fibers.
  • Synaptic pruning was distinct in the PFC (higher spine density) and DS (opposite effect), and the mutation altered microglial inflammatory responses.

Conclusions:

  • The LRRK2 G2019S mutation triggers inflammatory cytokine production and abnormal microglial activity.
  • This results in aberrant phagocytosis, synaptic pruning, and DAergic fiber loss during aging, contributing to PD-related behavioral abnormalities.
Keywords:
Abnormal behaviorsDAergic fiber refinementLRRK2 G2019S mutationMicrogliaSynaptic pruning

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