Dexamethasone induces the expression of LRRK2 and α-synuclein, two genes that when mutated cause Parkinson's disease in an autosomal dominant manner

Park, Ji-Min; Ho, Dong Hwan; Yun, Hye Jin; Kim, Hye-Jung; Lee, Chan Hong; Park, Sung Woo; Kim, Young Hoon; Son, Ilhong; Seol, Wongi

doi:10.5483/bmbrep.2013.46.9.234

Cited by 9 publications

(6 citation statements)

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“…The human neuroblastoma SH-SY5Y cell line is one of the most widely used dopaminergic cellular models with differentiation by retinoic acid. Moreover, treatment of cells with retinoic acid significantly increases LRRK2 expression [ 43 ] with little difference of p53 expression, increasing the possibility for LRRK2-mediated p53 phosphorylation (Additional file 2 : Figure S2). The differentiated cell lysates were co-immunoprecipitated with the p53 or LRRK2 antibody.…”

Section: Resultsmentioning

confidence: 99%

Leucine-Rich Repeat Kinase 2 (LRRK2) phosphorylates p53 and induces p21WAF1/CIP1 expression

Kim

et al. 2015

Mol Brain

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BackgroundLeucine-rich repeat kinase 2 (LRRK2) is a gene in which a mutation causes Parkinson’s disease (PD), and p53 is a prototype tumor suppressor. In addition, activation of p53 in patient with PD has been reported by several studies. Because phosphorylation of p53 is critical for regulating its activity and LRRK2 is a kinase, we tested whether p53 is phosphorylated by LRRK2.ResultsLRRK2 phosphorylates threonine (Thr) at TXR sites in an in vitro kinase assay, and the T304 and T377 were identified as putative phosphorylated residues. An increase of phospho-Thr in the p53 TXR motif was confirmed in the cells overexpressing G2019S, and human induced pluripotent stem (iPS) cells of a G2019S carrier. Interactions between LRRK2 and p53 were confirmed by co-immunoprecipitation of lysates of differentiated SH-SY5Y cells. LRRK2 mediated p53 phosphorylation translocalizes p53 predominantly to nucleus and increases p21WAF1/CIP1 expression in SH-SY5Y cells based on reverse transcription-polymerase chain reaction and Western blot assay results. The luciferase assay using the p21WAF1/CIP1 promoter-reporter also confirmed that LRRK2 kinase activity increases p21 expression. Exogenous expression of G2019S and the phosphomimetic p53 T304/377D mutants increased expression of p21WAF1/CIP1 and cleaved PARP, and cytotoxicity in the same cells. We also observed increase of p21 expression in rat primary neuron cells after transient expression of p53 T304/377D mutants and the mid-brain lysates of the G2019S transgenic mice.Conclusionp53 is a LRRK2 kinase substrate. Phosphorylation of p53 by LRRK2 induces p21WAF1/CIP1 expression and apoptosis in differentiated SH-SY5Y cells and rat primary neurons.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-015-0145-7) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Leucine-Rich Repeat Kinase 2 (LRRK2) phosphorylates p53 and induces p21WAF1/CIP1 expression

Kim

et al. 2015

Mol Brain

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“…This finding is in accordance with a recent study, which showed that dexamethasone increased the expression of two genes implicated in Parkinson's disease, the LRRK2 and α-synuclein. 36 Our study has some limitations. Our sample of 11 glucocorticoid-sensitive and 11 glucocorticoid-resistant subjects is small.…”

Section: Glucocorticoid-resistant (N = 11)mentioning

confidence: 89%

Transcriptomics in tissue glucocorticoid sensitivity

Nicolaides

Polyzos

Koniari

et al. 2019

Eur J Clin Investigation

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Background: Synthetic glucocorticoids are widely used in the treatment of several inflammatory, autoimmune and lymphoproliferative disorders. However, considerable variation in response to therapeutic doses of glucocorticoids has been documented among individuals. The aim of our study was to identify novel glucocorticoid sensitivity-determining genes using genome-wide expression profiling in healthy subjects. Methods: One hundred one healthy subjects [mean age ± standard error of the mean (SEM); 26.52 ± 0.50 years] were given 0.25 mg dexamethasone at midnight, and serum cortisol concentrations were determined at 08:00 hours the following morning.Subjects were stratified into the 10% most glucocorticoid-sensitive and 10% most glucocorticoid-resistant according to the serum cortisol concentrations. Genomic DNA, RNA and plasma samples were obtained in the 22 subjects one month later. Results: Transcriptomic analysis showed variability between glucocorticoid-resistant and glucocorticoid-sensitive subjects. One hundred thirty-three genes were upregulated and 49 downregulated in the glucocorticoid-resistant compared to the glucocorticoid-sensitive group. Further analysis revealed differences between 3 glucocorticoid-resistant and 3 glucocorticoid-sensitive subjects. The majority of the 1058 upregulated genes and 1139 downregulated genes were found to participate in telomere maintenance, systemic lupus erythematosus and Alzheimer's disease.Interestingly, Synuclein A, a key molecule in Parkinson's disease, was upregulated in the subgroup of glucocorticoid-sensitive subjects. Conclusions: We have identified differences in tissue sensitivity to glucocorticoids among healthy subjects at the transcriptomic level. These differences are associated with differential expression of genes related to autoimmune and neurological disorders. K E Y W O R D Sglucocorticoid receptor, glucocorticoids, RNA sequencing, telomere length, tissue glucocorticoid sensitivity, transcriptomics

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“…There is in vitro evidence implicating a role of disrupted GR signaling in PD molecular pathology. Administration of DEX to dopaminergic neurons disrupted GR signaling, resulting in an upregulation of α-synuclein protein levels ( 338 ). GC-mediated upregulation of α-synuclein levels has also been reported in peripheral blood mononuclear cells cultured from PD patients ( 339 ).…”

Section: Depression In Parkinson’s Diseasementioning

confidence: 99%

Is Dysregulation of the HPA-Axis a Core Pathophysiology Mediating Co-Morbid Depression in Neurodegenerative Diseases?

2015

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There is increasing evidence of prodromal manifestation of neuropsychiatric symptoms in a variety of neurodegenerative diseases such as Parkinson’s disease (PD) and Huntington’s disease (HD). These affective symptoms may be observed many years before the core diagnostic symptoms of the neurological condition. It is becoming more apparent that depression is a significant modifying factor of the trajectory of disease progression and even treatment outcomes. It is therefore crucial that we understand the potential pathophysiologies related to the primary condition, which could contribute to the development of depression. The hypothalamic–pituitary–adrenal (HPA)-axis is a key neuroendocrine signaling system involved in physiological homeostasis and stress response. Disturbances of this system lead to severe hormonal imbalances, and the majority of such patients also present with behavioral deficits and/or mood disorders. Dysregulation of the HPA-axis is also strongly implicated in the pathology of major depressive disorder. Consistent with this, antidepressant drugs, such as the selective serotonin reuptake inhibitors have been shown to alter HPA-axis activity. In this review, we will summarize the current state of knowledge regarding HPA-axis pathology in Alzheimer’s, PD and HD, differentiating between prodromal and later stages of disease progression when evidence is available. Both clinical and preclinical evidence will be examined, but we highlight animal model studies as being particularly useful for uncovering novel mechanisms of pathology related to co-morbid mood disorders. Finally, we purpose utilizing the preclinical evidence to better inform prospective, intervention studies.

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Dexamethasone induces the expression of LRRK2 and α-synuclein, two genes that when mutated cause Parkinson's disease in an autosomal dominant manner

Cited by 9 publications

References 30 publications

Leucine-Rich Repeat Kinase 2 (LRRK2) phosphorylates p53 and induces p21WAF1/CIP1 expression

Leucine-Rich Repeat Kinase 2 (LRRK2) phosphorylates p53 and induces p21WAF1/CIP1 expression

Transcriptomics in tissue glucocorticoid sensitivity

Is Dysregulation of the HPA-Axis a Core Pathophysiology Mediating Co-Morbid Depression in Neurodegenerative Diseases?

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