Genetic analysis of α‐synuclein 3′ untranslated region and its corresponding microRNAs in relation to Parkinson's disease compared to dementia with Lewy bodies

Tagliafierro, Lidia; Glenn, Omolara Chinue; Zamora, Madison E.; Beach, Thomas G.; Woltjer, Randy; Lutz, Michael W.; Chiba‐Falek, Ornit

doi:10.1016/j.jalz.2017.03.001

Cited by 27 publications

(29 citation statements)

References 45 publications

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“…Expression levels of miR-153, miR-223 and the gene encoding α-synuclein, SNCA are highest in midbrain, 31,37,38 although they have also been detected in extracellular compartments, including blood, 34,39,40 CSF, 35,41 and saliva, 12,16,42 where their levels appear to fluctuate in response to disease state. Several groups, including our own, have linked miR-153 and, to a lesser extent, miR-223 to PD pathology.…”

Section: Discussionmentioning

confidence: 99%

Salivary microR‐153 and microR‐223 Levels as Potential Diagnostic Biomarkers of Idiopathic Parkinson's Disease

et al. 2019

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Background Parkinson's disease (PD) is the most common movement disorder among adults, affecting 2% of the world population older than 65 years of age. No diagnostic biomarker for routine use in clinical settings currently exists. Dysregulation of microRNAs (miRNAs) has been implicated in various neurodegenerative conditions, including PD. Distinct miRNAs have been demonstrated to be involved in the regulation of α‐synuclein, a key player in PD pathogenesis; miR‐153 and miR‐223 are downregulated in the brain and serum of parkinsonian GFAP.HMOX1 transgenic mice where they directly regulate α‐synuclein. Objective To ascertain whether salivary miR‐153 and miR‐223 are similarly downmodulated in, and may serve as diagnostic biomarkers of, idiopathic PD. Methods Using reverse transcriptase quantitative polymerase chain reaction, miR‐153 and miR‐223 levels were evaluated in the saliva of 77 non‐neurological controls and 83 PD patients. Levels of heme oxygenase‐1 and α‐synuclein were measured using enzyme‐linked immunosorbent assay. Analyses were adjusted by age, sex, medication exposure, disease duration, and relevant comorbidities. Results Log‐transformed expression levels of miR‐153 and miR‐223 were significantly decreased in the saliva of human PD patients in comparison with nonneurological controls. The miRNA expression levels did not change as a function of disease progression (Hoehn and Yahr staging). The area under the receiver operating characteristic curve separating controls from PD patients was 79% (95% confidence interval, 61%–96%) for miR‐153 and 77% (95% confidence interval, 59%–95%) for miR‐223. The ratios of miRNAs to oligomeric α‐synuclein, total α‐synuclein, or heme oxygenase‐1 protein did not improve accuracy of the test. Conclusion Salivary miR‐153 and miR‐223 levels may serve as useful, noninvasive, and relatively inexpensive diagnostic biomarkers of idiopathic PD. © 2019 International Parkinson and Movement Disorder Society

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Section: Discussionmentioning

confidence: 99%

Salivary microR‐153 and microR‐223 Levels as Potential Diagnostic Biomarkers of Idiopathic Parkinson's Disease

et al. 2019

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“…In the GFAP.HMOX1 mice, astroglial HO‐1 overexpression engenders significant downregulation of both neural and circulating miR‐153 and miR‐223 which, in turn, de‐repress the Snca gene in brain and potentially peripheral tissues (erythrocytes). Conserved binding sites for miR‐153 and miR‐223 were predicted to lie within the SNCA 3'UTR (partial complementarity) across species using the TargetScan software, and both miRNAs are highly expressed in rodent and human brain (Farh et al, ; Tagliafierro et al, ). miR‐153 was confirmed to bind the 3'UTR of SNCA and suppress α‐synuclein mRNA and protein levels (Doxakis, ).…”

Section: Discussionmentioning

confidence: 99%

GlialHMOX1expression promotes central and peripheral α‐synuclein dysregulation and pathogenicity in parkinsonian mice

Cressatti

Song

Turk

et al. 2019

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α‐Synuclein is a key player in the pathogenesis of Parkinson disease (PD). Expression of human heme oxygenase‐1 (HO‐1) in astrocytes of GFAP.HMOX1 transgenic (TG) mice between 8.5 and 19 months of age results in a parkinsonian phenotype characterized by neural oxidative stress, nigrostriatal hypodopaminergia associated with locomotor incoordination, and overproduction of α‐synuclein. We identified two microRNAs (miR‐), miR‐153 and miR‐223, that negatively regulate α‐synuclein in the basal ganglia of male and female GFAP.HMOX1 mice. Serum concentrations of both miRNAs progressively declined in the wild‐type (WT) and GFAP.HMOX1 mice between 11 and 19 months of age. Moreover, at each time point surveyed, circulating levels of miR‐153 were significantly lower in the TG animals compared to WT controls, while α‐synuclein protein concentrations were elevated in erythrocytes of the GFAP.HMOX1 mice at 19 months of age relative to WT values. Primary WT neurons co‐cultured with GFAP.HMOX1 astrocytes exhibited enhanced protein oxidation, mitophagy and apoptosis, aberrant expression of genes regulating the dopaminergic phenotype, and an imbalance in gene expression profiles governing mitochondrial fission and fusion. Many, but not all, of these neuronal abnormalities were abrogated by small interfering RNA (siRNA) knockdown of α‐synuclein, implicating α‐synuclein as a potent, albeit partial, mediator of HO‐1's neurodystrophic effects in these parkinsonian mice. Overexpression of HO‐1 in stressed astroglia has previously been documented in the substantia nigra of idiopathic PD and may promote α‐synuclein production and toxicity by downmodulating miR‐153 and/or miR‐223 both within the CNS and in peripheral tissues.

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“…Analysis of the double-stained cells confirmed the reduction in the endogenous a-synuclein levels, amounting to $36% lower levels in the gRNA4 MD NPC line versus the control no-gRNA line (p < 0.0001, Student's t test) ( Figures 4D-4H). Of note, the successful differentiation rate of MD NPC is $80%, 32 and this may explain the greater effect on a-synuclein levels observed by the double immunocytochemistry approach, as it constrained the analysis to the differentiated neurons only versus western blot and real-time PCR analyses that comprised the whole cell culture ( Figure S1).…”

Section: Downregulation Of Snca Mrna and Protein Levelsmentioning

confidence: 99%

Downregulation of SNCA Expression by Targeted Editing of DNA Methylation: A Potential Strategy for Precision Therapy in PD

et al. 2018

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Elevated levels of SNCA have been implicated in the pathogenesis of Parkinson's disease (PD), while normal physiological levels of SNCA are needed to maintain neuronal function. We ought to develop new therapeutic strategies targeting the regulation of SNCA expression. DNA methylation at SNCA intron 1 regulates SNCA transcription, and PD brains showed differential methylation levels compared to controls. Thus, DNA methylation at SNCA intron 1 is an attractive target for fine-tuned downregulation of SNCA levels. Here we developed a system, comprising an all-in-one lentiviral vector, for targeted DNA methylation editing within intron 1. The system is based on CRISPR-deactivated Cas9 (dCas9) fused with the catalytic domain of DNA-methyltransferase 3A (DNMT3A). Applying the system to human induced pluripotent stem cell (hiPSC)-derived dopaminergic neurons from a PD patient with the SNCA triplication resulted in fine downregulation of SNCA mRNA and protein mediated by targeted DNA methylation at intron 1. Furthermore, the reduction in SNCA levels by the guide RNA (gRNA)-dCas9-DMNT3A system rescued disease-related cellular phenotype characteristics of the SNCA triplication hiPSC-derived dopaminergic neurons, e.g., mitochondrial ROS production and cellular viability. We established that DNA hypermethylation at SNCA intron 1 allows an effective and sufficient tight downregulation of SNCA expression levels, suggesting the potential of this target sequence combined with the CRISPR-dCas9 technology as a novel epigenetic-based therapeutic approach for PD.

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Genetic analysis of α‐synuclein 3′ untranslated region and its corresponding microRNAs in relation to Parkinson's disease compared to dementia with Lewy bodies

Cited by 27 publications

References 45 publications

Salivary microR‐153 and microR‐223 Levels as Potential Diagnostic Biomarkers of Idiopathic Parkinson's Disease

Salivary microR‐153 and microR‐223 Levels as Potential Diagnostic Biomarkers of Idiopathic Parkinson's Disease

GlialHMOX1expression promotes central and peripheral α‐synuclein dysregulation and pathogenicity in parkinsonian mice

Downregulation of SNCA Expression by Targeted Editing of DNA Methylation: A Potential Strategy for Precision Therapy in PD

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