RETRACTED: PINK1 regulates histone H3 trimethylation and gene expression by interaction with the polycomb protein EED/WAIT1

Berthier, Arnaud; Jiménez-Sáinz, Judit; Pulido, Rafael

doi:10.1073/pnas.1216844110

Cited by 15 publications

(7 citation statements)

References 49 publications

(65 reference statements)

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“…These biological processes have been implicated in the pathogenesis of PD before [ 8 – 10 ]. Proteins encoded by other differentially expressed mRNAs are important players in other processes that have been implicated in DA neuronal dysregulation and death, including cytoplasmic and nuclear cascades regulating (vesicular) trafficking [ 11 ], mitochondrial function and apoptosis [ 12 ], proteosomal degradation (including the degradation of DA neuron-specific transcription factors) [ 13 ], as well as transcriptional, posttranscriptional and translational processes such as histone regulation [ 14 ] and pre-mRNA splicing [ 15 ].…”

Section: Discussionmentioning

confidence: 99%

Validity of the MPTP-Treated Mouse as a Model for Parkinson’s Disease

et al. 2015

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Parkinson’s disease (PD) is characterized by dopaminergic (DA) neuron death in the substantia nigra (SN) and subsequent striatal adaptations. Mice treated with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrimidine (MPTP) are widely used as a model for PD. To assess the validity of the MPTP mouse model for PD pathogenesis, we here identify the biological processes that are dysregulated in both human PD and MPTP-treated mice. Gene enrichment analysis of published differentially expressed messenger RNAs (mRNAs) in the SN of PD patients and MPTP-treated mice revealed an enrichment of gene categories related to motor dysfunction and neurodegeneration. In the PD striatum, a similar enrichment was found, whereas in the striatum of MPTP mice, acute processes linked to epilepsy were selectively enriched shortly following MPTP treatment. More importantly, we integrated the proteins encoded by the differentially expressed mRNAs into molecular landscapes showing PD pathogenesis-implicated processes only in the SN, including vesicular trafficking, exocytosis, mitochondrial apoptosis, and DA neuron-specific transcription, but not in the striatum. We conclude that the current use of the MPTP mouse as a model for studying the molecular processes in PD pathogenesis is more valid for SN than striatal mechanisms in PD. This novel insight has important practical implications for future studies using this model to investigate PD pathogenesis and evaluate the efficacy of new treatments.Electronic supplementary materialThe online version of this article (doi:10.1007/s12035-015-9103-8) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Validity of the MPTP-Treated Mouse as a Model for Parkinson’s Disease

et al. 2015

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“…PINK1 has recently been shown to interact with and phosphorylate the embryonic ectoderm development polycomb histone-methylation modulator, redistributing it to the mitochondria, resulting in a favorable change in transcription regulation for neuronal differentiation [74]. PINK1 downregulation in zebrafish results in delayed brain development, enlarged ventricles and a moderate decrease in TH-positive neurons in the diencephalon, likely due to an increase in apoptosis as evidenced by an increase in active Caspase 3 in these embryos [75].…”

Section: Evidence For a Developmental Component Of Pd: Deregulated Emmentioning

confidence: 99%

Neural stem cells in Parkinson’s disease: a role for neurogenesis defects in onset and progression

Grand

Gonzalez-Cano

Pavlou

et al. 2014

Cell. Mol. Life Sci.

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Parkinson's disease (PD) is the second most common neurodegenerative disorder, leading to a variety of motor and non-motor symptoms. Interestingly, nonmotor symptoms often appear a decade or more before the first signs of motor symptoms. Some of these non-motor symptoms are remarkably similar to those observed in cases of impaired neurogenesis and several PD-related genes have been shown to play a role in embryonic or adult neurogenesis. Indeed, animal models deficient in Nurr1, Pitx3, SNCA and PINK1 display deregulated embryonic neurogenesis and LRRK2 and VPS35 have been implicated in neuronal development-related processes such as Wnt/bcatenin signaling and neurite outgrowth. Moreover, adult neurogenesis is affected in both PD patients and PD animal models and is regulated by dopamine and dopaminergic (DA) receptors, by chronic neuroinflammation, such as that observed in PD, and by differential expression of wild-type or mutant forms of PD-related genes. Indeed, an increasing number of in vivo studies demonstrate a role for SNCA and LRRK2 in adult neurogenesis and in the generation and maintenance of DA neurons. Finally, the roles of PDrelated genes, SNCA, LRRK2, VPS35, Parkin, PINK1 and DJ-1 have been studied in NSCs, progenitor cells and induced pluripotent stem cells, demonstrating a role for some of these genes in stem/progenitor cell proliferation and maintenance. Together, these studies strongly suggest a link between deregulated neurogenesis and the onset and progression of PD and present strong evidence that, in addition to a neurodegenerative disorder, PD can also be regarded as a developmental disorder.

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“…The most significantly enriched sets are associated with metabolism and mitochondrial function, neuronal transmitters and serotonin, epigenetic modifications, and the transcription factor FOXP3 (Additional file 1 : Table S1). Each of these categories has some previously discovered association with PD, although not through traditional gene set methods (metabolism and mitochondrial function [ 22 ]; neuronal transmitters and serotonin [ 26 ]; epigenetic modifications [ 27 ]; FOXP3 [ 28 ]). Through our new gene set enrichment method, we discovered a relationship between the expression of these gene sets and PD.…”

Section: Resultsmentioning

confidence: 99%

Moment based gene set tests

Larson¹,

Owen

2015

BMC Bioinformatics

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BackgroundPermutation-based gene set tests are standard approaches for testing relationships between collections of related genes and an outcome of interest in high throughput expression analyses. Using M random permutations, one can attain p-values as small as 1/(M+1). When many gene sets are tested, we need smaller p-values, hence larger M, to achieve significance while accounting for the number of simultaneous tests being made. As a result, the number of permutations to be done rises along with the cost per permutation. To reduce this cost, we seek parametric approximations to the permutation distributions for gene set tests.ResultsWe study two gene set methods based on sums and sums of squared correlations. The statistics we study are among the best performers in the extensive simulation of 261 gene set methods by Ackermann and Strimmer in 2009. Our approach calculates exact relevant moments of these statistics and uses them to fit parametric distributions. The computational cost of our algorithm for the linear case is on the order of doing |G| permutations, where |G| is the number of genes in set G. For the quadratic statistics, the cost is on the order of |G|2 permutations which can still be orders of magnitude faster than plain permutation sampling. We applied the permutation approximation method to three public Parkinson’s Disease expression datasets and discovered enriched gene sets not previously discussed. We found that the moment-based gene set enrichment p-values closely approximate the permutation method p-values at a tiny fraction of their cost. They also gave nearly identical rankings to the gene sets being compared.ConclusionsWe have developed a moment based approximation to linear and quadratic gene set test statistics’ permutation distribution. This allows approximate testing to be done orders of magnitude faster than one could do by sampling permutations.We have implemented our method as a publicly available Bioconductor package, npGSEA (www.bioconductor.org).Electronic supplementary materialThe online version of this article (doi:10.1186/s12859-015-0571-7) contains supplementary material, which is available to authorized users.

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RETRACTED: PINK1 regulates histone H3 trimethylation and gene expression by interaction with the polycomb protein EED/WAIT1

Cited by 15 publications

References 49 publications

Validity of the MPTP-Treated Mouse as a Model for Parkinson’s Disease

Validity of the MPTP-Treated Mouse as a Model for Parkinson’s Disease

Neural stem cells in Parkinson’s disease: a role for neurogenesis defects in onset and progression

Moment based gene set tests

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