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

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.

LRRK2 regulates synaptic function through BDNF signaling and actin cytoskeleton

“…By binding to receptor tyrosine kinases, cognate neurotrophic factors plastically shape neuronal activity 40 . Brain-derived neurotrophic factor (BDNF) is particularly important to modulate cortico-striatal neurotransmission 41 , a circuitry relevant for PD where LRRK2 expression is higher compared to other brain regions 42,43 . To address whether LRRK2 Ser935 phosphorylation is stimulated by BDNF, we prepared primary mouse cortical neurons from C57BL/6J wild-type mice and stimulated them with 100 ng/ml of BDNF at days in vitro 14 (DIV14) when synapses are fully functional ( Figure 1a ) and LRRK2 expression is detectable 44 .…”

Animal model for high consumption and preference of ethanol and its interplay with high sugar and butter diet, behavior, and neuroimmune system

“…In this context, our research group identified relations of the Lrrk2 gene, until then associated with Parkinson’s and inflammatory bowel diseases, in preference behavior and loss of control by alcohol in mice, Zebrafish, and humans ( 31 , 32 , 36 , 108 – 110 ). This gene is involved in neural processes, such as the reuptake of synaptic components and synaptic plasticity, and in several signaling pathways by performing GTPase and kinase functions, which influence processes such as cell proliferation and differentiation, apoptosis, inflammation, and immune response ( 50 , 111 – 116 ). Evidence in humans and mice corroborates with the results of this study regarding the differential regulation with Lrrk2 downregulation to alcohol intake.…”

FOXP1 regulates the development of excitatory synaptic inputs onto striatal neurons and induces phenotypic reversal with reinstatement

“…In fact, some of these genes may have been more relevant to embryonic deletion as compared to the obvious receptor and scaffolding candidates discussed above. For example, Leucine-rich repeat kinase 2 ( Lrkk2 ) is highly expressed in the SPNs 48, 70–72 and plays a critical role in regulating synaptogenesis and corticostriatal glutamatergic synaptic function 47, 73, 74 . Another gene of interest, Protein phosphatase 1 regulatory inhibitor subunit 1B ( Ppp1r1b, also known as DARPP32) is critical for the corticostriatal synaptic plasticity and controls both long term potentiation and depression in the striatum 44–46 .…”