Dataset Information

Polymorphisms of Dopamine Receptor Genes and Risk of L-Dopa-Induced Dyskinesia in Parkinson's Disease.

ABSTRACT: L-dopa-induced dyskinesia (LID) is a frequent motor complication of Parkinson's disease (PD), associated with a negative prognosis. Previous studies showed an association between dopamine receptor (DR) gene (DR) variants and LID, the results of which have not been confirmed. The present study is aimed to determine whether genetic differences of DR are associated with LID in a small but well-characterized cohort of PD patients. To this end we enrolled 100 PD subjects, 50 with and 50 without LID, matched for age, gender, disease duration and dopaminergic medication in a case-control study. We conducted polymerase chain reaction for single nucleotide polymorphisms (SNP) in both D1-like (DRD1A48G; DRD1C62T and DRD5T798C) and D2-like DR (DRD2G2137A, DRD2C957T, DRD3G25A, DRD3G712C, DRD4C616G and DRD4nR VNTR 48bp) analyzed genomic DNA. Our results showed that PD patients carrying allele A at DRD3G3127A had an increased risk of LID (OR 4.9; 95% CI 1.7-13.9; p = 0.004). The present findings may provide valuable information for personalizing pharmacological therapy in PD patients.

SUBMITTER: Comi C

PROVIDER: S-EPMC5343779 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Publications

Polymorphisms of Dopamine Receptor Genes and Risk of L-Dopa-Induced Dyskinesia in Parkinson's Disease.

Comi Cristoforo C Ferrari Marco M Marino Franca F Magistrelli Luca L Cantello Roberto R Riboldazzi Giulio G Bianchi Maria Laura Ester ML Bono Giorgio G Cosentino Marco M

International journal of molecular sciences 20170124 2

L-dopa-induced dyskinesia (LID) is a frequent motor complication of Parkinson's disease (PD), associated with a negative prognosis. Previous studies showed an association between dopamine receptor (DR) gene (<i>DR</i>) variants and LID, the results of which have not been confirmed. The present study is aimed to determine whether genetic differences of <i>DR</i> are associated with LID in a small but well-characterized cohort of PD patients. To this end we enrolled 100 PD subjects, 50 with and 50 ...[more]

PMID: 28125015

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Project description:The striatum is the main structure of the basal ganglia. The striatum receives inputs from various cortical areas, and its subregions play distinct roles in motor and emotional functions. Recently, striatal maps based on corticostriatal connectivity and striosome-matrix compartmentalization were developed, and we were able to subdivide the striatum into seven subregions. Dopaminergic modulation of the excitability of medium spiny neurons (MSNs) is critical for striatal function. In this study, we investigated the functional properties of dopamine signaling in seven subregions of the striatum from male mice. By monitoring the phosphorylation of PKA substrates including DARPP-32 in mouse striatal slices, we identified two subregions with low D1 receptor signaling: the dorsolateral portion of the intermediate/rostral part (DL-IR) and the intermediate/caudal part (IC). Low D1 receptor signaling in the two subregions was maintained by phosphodiesterase (PDE)10A and muscarinic M4 receptors. In an animal model of 6-hydroxydopamine (6-OHDA)-induced hemi-parkinsonism, D1 receptor signaling was upregulated in almost all subregions including the DL-IR, but not in the IC. When L-DOPA-induced dyskinesia (LID) was developed, D1 receptor signaling in the IC was upregulated and correlated with the severity of LID. Our results suggest that the function of the striatum is maintained through the subregion-specific regulation of dopamine D1 receptor signaling and that the aberrant activation of D1 receptor signaling in the IC is involved in LID. Future studies focusing on D1 receptor signaling in the IC of the striatum will facilitate the development of novel therapeutics for LID.SIGNIFICANCE STATEMENT Recent progress in striatal mapping based on corticostriatal connectivity and striosome-matrix compartmentalization allowed us to subdivide the striatum into seven subregions. Analyses of D1 receptor signaling in the seven subregions identified two unique subregions with low D1 receptor signaling: the dorsolateral portion of the intermediate/rostral part (DL-IR) and the intermediate/caudal part (IC). Aberrant activation of D1 receptor signaling in the IC is involved in L-DOPA-induced dyskinesia (LID). Previous studies of LID have mainly focused on the DL-IR, but not on the IC of the striatum. Future studies to clarify aberrant D1 receptor signaling in the IC are required to develop novel therapeutics for LID.

Dataset Information

Polymorphisms of Dopamine Receptor Genes and Risk of L-Dopa-Induced Dyskinesia in Parkinson's Disease.

Publications

Polymorphisms of Dopamine Receptor Genes and Risk of L-Dopa-Induced Dyskinesia in Parkinson's Disease.

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