Dopamine Signaling Leads to Loss of Polycomb Repression and Aberrant Gene Activation in Experimental Parkinsonism

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In Parkinson's disease (PD) the motor impairment produced by the progressive death of midbrain dopaminergic neurons is commonly treated with the dopamine precursor, L-DOPA. Utilizing a mouse model of PD, we show that L-DOPA, via activation of dopamine D1 receptors, promotes the expression of genes normally repressed by Polycomb group (PcG) proteins. We propose that this effect is exerted by promoting the phosphorylation of histone H3 on serine 28 at genomic regions marked by tri-methylation of the adjacent lysine 27, generating a H3K27me3S28p double-mark. This event leads to displacement of PcG proteins and aberrant gene expression. These findings reveal a previously unrecognized plasticity of PcG-repressed genes in terminally differentiated neurons. Furthermore, the identification of specific genes whose expression is increased upon prolonged treatment with L-DOPA and the consequential activation of dopamine D1 receptors offer a possibility to design novel therapeutic strategies to treat Parkinson's disease and potentially other disorders caused by dysfunctional dopaminergic transmission in the brain, such as drug addiction and schizophrenia.

Vyšlo v časopise: Dopamine Signaling Leads to Loss of Polycomb Repression and Aberrant Gene Activation in Experimental Parkinsonism. PLoS Genet 10(9): e32767. doi:10.1371/journal.pgen.1004574
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004574

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