Aging, Environment, & DiseaseHistone Modifications

Dopamine signaling leads to loss of polycomb repression and aberrant gene activation in experimental parkinsonism

localization of H3K27me3S28p pictureParkinson’s disease (PD) is the second most frequent neurodegenerative disease, affecting 1-2% of the population over 55 years of age. The main pathological feature of PD is the progressive death of neurons located in the midbrain that produce the neurotransmitter dopamine.  These neurons modulate the activity of a collection of nuclei, termed the basal ganglia, which influence motor output.  The consequent loss of dopamine in these regions results in the emergence of motor impairments, such as tremor and bradykinesia. Systemic administration of the dopamine precursor, L-DOPA, is currently the most effective intervention for the treatment of these symptoms, particularly during the initial phase of PD1. For reasons that are poorly understood, prolonged use of this drug is accompanied by the development of uncontrollable choreic and dystonic movements, or dyskinesia, which represent one of the major hindrances to the pharmacotherapy of PD2.

L-DOPA-induced dyskinesia has been associated to abnormal transmission of dopamine D1 receptors (D1Rs), which are highly expressed in the striatum, the major component of the basal ganglia3. Following conversion to dopamine, L-DOPA acts on sensitized D1Rs to stimulate the cAMP/dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) as well as the extracellular signal-regulated kinases (ERK) signaling cascades. Phosphorylation catalyzed by cAMP-dependent protein kinase converts DARPP-32 into an inhibitor of protein phosphatase-1 (PP-1)4. In addition, augmented ERK activity leads to the phosphorylation of the mitogen- and stress-activated kinase 1 (MSK1). Both DARPP-32 and MSK1 have been implicated in dyskinesia5,6, but little is known about the effects produced by L-DOPA downstream of these signaling components. Our laboratories have examined the effects of L-DOPA on histone marks associated to the regulation of Polycomb group (PcG) proteins, which are known to bind to and repress specific subsets of genes in embryonic stem cells and during lineage commitment to the terminal differentiated state7.

Using a mouse model of PD, we show that administration of L-DOPA increases the phosphorylation of histone H3 on serine 28 (S28p) at genomic regions marked by trimethylation of the adjacent lysine 27 (K27me3). Experiments performed in transgenic mice expressing EGFP in distinct populations of neurons indicate that the induction of H3K27me3S28p occurs in a large group of medium spiny neurons that are enriched in D1Rs.  Importantly, the effect of L-

Work in human fibroblasts indicate that H3K27me3S28p de-represses genes silenced by PcG proteins8. In line with this observation, chromatin immunoprecipitation (ChIP) experiments show that increased H3K27me3S28p is accompanied by reduced PcG binding to regulatory regions of genes. An analysis of the genome-wide distribution of L-DOPA-induced H3K27me3S28p by ChIP sequencing (ChIP-seq) in combination with expression analysis by RNA-sequencing (RNA-seq) show that the induction of H3K27me3S28p correlates with increased expression of a subset of PcG-repressed genes. Moreover, enhanced H3K27me3S28p persists during chronic L-DOPA administration, which is linked to the development of dyskinesia, and correlates with aberrant gene expression. Interestingly, we observed that certain genes are only induced in response to chronic administration of L-DOPA.DOPA is reduced by genetic inactivation of DARPP-32 and MSK1. These results show that activation of D1Rs enhances H3K27me3S28p via MSK1-mediated phosphorylation of S28 and concomitant DARPP-32-mediated inhibition o
f dephosphorylation.  This latter conclusion is supported by experiments in vitro showing that PP-1 is able to dephosphorylate histone H3 peptides modified with S28p or K27me3S28p.

These findings reveal a previously unrecognized plasticity of PcG repressed genes in terminally differentiated neurons. We propose that dopaminergic transmission can activate PcG repressed genes in the adult brain and thereby contribute to long-term maladaptive responses including the motor complications caused by prolonged administration of L-DOPA in PD.

Södersten E, Feyder M, Lerdrup M, Gomes AL, Kryh H, Spigolon G, Caboche J, Fisone G, & Hansen K (2014). Dopamine signaling leads to loss of polycomb repression and aberrant gene activation in experimental parkinsonism. PLoS genetics, 10 (9) PMID: 25254549

1.  Birkmayer W, & Hornykiewicz O (1998). The effect of l-3,4-dihydroxyphenylalanine (=DOPA) on akinesia in parkinsonism. Parkinsonism & related disorders, 4 (2), 59-60 PMID: 18591089

2.  Obeso, J., Olanow, C., & Nutt, J. (2000). Levodopa motor complications in Parkinson’s disease Trends in Neurosciences, 23 DOI: 10.1016/S1471-1931(00)00031-8

3.  Feyder M, Bonito-Oliva A, & Fisone G (2011). L-DOPA-Induced Dyskinesia and Abnormal Signaling in Striatal Medium Spiny Neurons: Focus on Dopamine D1 Receptor-Mediated Transmission. Frontiers in behavioral neuroscience, 5 PMID: 22028687

4.  Greengard, P. (2001). The Neurobiology of Slow Synaptic Transmission Science, 294 (5544), 1024-1030 DOI: 10.1126/science.294.5544.1024

5.  Feyder M, Södersten E, Santini E, Vialou V, LaPlant Q, Watts EL, Spigolon G, Hansen K, Caboche J, Nestler EJ, & Fisone G (2014). A Role for Mitogen- and Stress-Activated Kinase 1 in L-DOPA-Induced Dyskinesia and ∆FosB Expression. Biological psychiatry PMID: 25193242

6.  Santini E, Valjent E, Usiello A, Carta M, Borgkvist A, Girault JA, Hervé D, Greengard P, & Fisone G (2007). Critical involvement of cAMP/DARPP-32 and extracellular signal-regulated protein kinase signaling in L-DOPA-induced dyskinesia. The Journal of neuroscience : the official journal of the Society for Neuroscience, 27 (26), 6995-7005 PMID: 17596448

7.  Di Croce, L., & Helin, K. (2013). Transcriptional regulation by Polycomb group proteins Nature Structural & Molecular Biology, 20 (10), 1147-1155 DOI: 10.1038/nsmb.2669

8. Gehani SS, Agrawal-Singh S, Dietrich N, Christophersen NS, Helin K, & Hansen K (2010). Polycomb group protein displacement and gene activation through MSK-dependent H3K27me3S28 phosphorylation. Molecular cell, 39 (6), 886-900 PMID: 20864036


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Gilberto Fisone

Gilberto Fisone