LRRK2 at Striatal Synapses: Cell-Type Specificity and Mechanistic Insights

Patrick D. Skelton, Valerie Tokars, Loukia Parisiadou*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

Abstract

Mutations in leucine-rich repeat kinase 2 (LRRK2) cause Parkinson’s disease with a similar clinical presentation and progression to idiopathic Parkinson’s disease, and common variation is linked to disease risk. Recapitulation of the genotype in rodent models causes abnormal dopamine release and increases the susceptibility of dopaminergic neurons to insults, making LRRK2 a valuable model for understanding the pathobiology of Parkinson’s disease. It is also a promising druggable target with targeted therapies currently in development. LRRK2 mRNA and protein expression in the brain is highly variable across regions and cellular identities. A growing body of work has demonstrated that pathogenic LRRK2 mutations disrupt striatal synapses before the onset of overt neurodegeneration. Several substrates and interactors of LRRK2 have been identified to potentially mediate these pre-neurodegenerative changes in a cell-type-specific manner. This review discusses the effects of pathogenic LRRK2 mutations in striatal neurons, including cell-type-specific and pathway-specific alterations. It also highlights several LRRK2 effectors that could mediate the alterations to striatal function, including Rabs and protein kinase A. The lessons learned from improving our understanding of the pathogenic effects of LRRK2 mutations in striatal neurons will be applicable to both dissecting the cell-type specificity of LRRK2 function in the transcriptionally diverse subtypes of dopaminergic neurons and also increasing our understanding of basal ganglia development and biology. Finally, it will inform the development of therapeutics for Parkinson’s disease.

Original languageEnglish (US)
Article number169
JournalCells
Volume11
Issue number1
DOIs
StatePublished - Jan 1 2022

Keywords

  • A-kinase adaptor protein (AKAP)
  • Cell-type specificity
  • Leucine-rich repeat kinase 2 (LRRK2)
  • Parkinson’s disease
  • Protein kinase A (PKA)
  • Striatum
  • Synapse

ASJC Scopus subject areas

  • Medicine(all)

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