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.
Highlights
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There is no male predominance across leucine-rich repeat kinase 2 (LRRK2)-Parkinson’s disease (PD) mutation carriers, unlike what is typically seen in sporadic PD cases [22]
There were pathway-specific effects; synapse strength on dSPNs returned to baseline after the induction protocol, while iSPNs expressed LTD instead of LTP. This is in contrast with experiments in the dorsal striatum of BAC-G2019S overexpressing mice, which have found that corticostriatal LTP induced by high-frequency stimulation under low-magnesium conditions was intact; in these experiments, LTD induced by high-frequency stimulation in normal-magnesium conditions was impaired [87]
Summary
Parkinson’s disease (PD) is a progressive neurodegenerative disorder clinically characterized by motor symptoms including resting tremor, bradykinesia, and postural and gait instability [1]. Understanding how LRRK2 dysfunction leads to PD will broadly inform the pathophysiological basis and therapeutic strategies in PD This is further supported by compelling evidence from genome-wide association studies showing that LRRK2 variants act as risk factors for sporadic disease [23]. SNPs at a locus on chromosome 12 were found to improve outcomes in Progressive Supranuclear Palsy while reducing the expression of LRRK2 [24,25] This finding potentially broadens the relevance of LRRK2 to neurodegenerative disease. In order to draw attention to this emerging frontier of LRRK2 biology, we discuss cell-type specificity of LRRK2 expression in the basal ganglia, the functional impacts of LRRK2 mutation in striatal cells, and several effectors and interactors that could potentially mediate the cell-type specificity of LRRK2 function
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