MicroRNAs to differentiate Parkinsonian disorders: Advances in biomarkers and therapeutics

Ramaswamy, Palaniswamy; Christopher, Rita; Pal, Pramod Kumar; Yadav, Ravi

doi:10.1016/j.jns.2018.08.032

Cited by 20 publications

(12 citation statements)

References 146 publications

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“…Recent work has emphasised the association of selected microRNAs to PD [27,122,123] and roles for microRNAs in neuroinflammation have received increased attention [25,124]. As neuroinflammation is thought to be a facilitator of PD pathogenesis, and was observed in the pre-motor PD model used in this study [32,125], we assessed changes in relative expression levels of three inflammatory and hypoxia associated microRNAs: miR21, miR155, and miR210.…”

Section: Discussionmentioning

confidence: 99%

Protein Deimination Signatures in Plasma and Plasma-EVs and Protein Deimination in the Brain Vasculature in a Rat Model of Pre-Motor Parkinson’s Disease

Sancandi¹,

Uysal-Onganer

Kraev

et al. 2020

IJMS

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The identification of biomarkers for early diagnosis of Parkinson's disease (PD) is of pivotal importance for improving approaches for clinical intervention. The use of translatable animal models of pre-motor PD therefore offers optimal opportunities for novel biomarker discovery in vivo. Peptidylarginine deiminases (PADs) are a family of calcium-activated enzymes that contribute to protein misfolding through post-translational deimination of arginine to citrulline. Furthermore, PADs are an active regulator of extracellular vesicle (EV) release. Both protein deimination and extracellular vesicles (EVs) are gaining increased attention in relation to neurodegenerative diseases, including in PD, while roles in pre-motor PD have yet to be investigated. The current study aimed at identifying protein candidates of deimination in plasma and plasma-EVs in a rat model of pre-motor PD, to assess putative contributions of such post-translational changes in the early stages of disease. EV-cargo was further assessed for deiminated proteins as well as three key micro-RNAs known to contribute to inflammation and hypoxia (miR21, miR155, and miR210) and also associated with PD. Overall, there was a significant increase in circulating plasma EVs in the PD model compared with sham animals and inflammatory and hypoxia related microRNAs were significantly increased in plasma-EVs of the pre-motor PD model. A significantly higher number of protein candidates were deiminated in the pre-motor PD model plasma and plasma-EVs, compared with those in the sham animals. KEGG (Kyoto encyclopedia of genes and genomes) pathways identified for deiminated proteins in the pre-motor PD model were linked to "Alzheimer's disease", "PD", "Huntington's disease", "prion diseases", as well as for "oxidative phosphorylation", "thermogenesis", "metabolic pathways", "Staphylococcus aureus infection", gap junction, "platelet activation", "apelin signalling", "retrograde endocannabinoid signalling", "systemic lupus erythematosus", and "non-alcoholic fatty liver disease". Furthermore, PD brains showed significantly increased staining for total deiminated proteins in the brain vasculature in cortex and hippocampus, as well as increased immunodetection of deiminated histone H3 in dentate gyrus and cortex. Our findings identify EVs and post-translational protein deimination as novel biomarkers in early pre-motor stages of PD. Figure 2. EV characterisation from rat plasma. (A) Representative Nanosight graphs showing nanoparticle tracking analysis (NTA) analysis of plasma EV profiles from sham-treated rats (Sham; n = 3). (B) Representative Nanosight graphs showing NTA analysis of plasma EV profiles from the premotor PD rat models (PD; n = 3). (C) Western blotting (WB) confirms that rat plasma-EVs are positive for the EV-specific markers CD63 and flotillin-1 (Flot-1); the molecular weight standard is indicated in kilo Daltons (kDa). (D,E) Transmission electron microscopy (TEM) images showing EVs isolated from sham (D) and pre-motor PD model (PD; (E)) rat plasma, revea...

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Section: Discussionmentioning

confidence: 99%

Protein Deimination Signatures in Plasma and Plasma-EVs and Protein Deimination in the Brain Vasculature in a Rat Model of Pre-Motor Parkinson’s Disease

Sancandi¹,

Uysal-Onganer

Kraev

et al. 2020

IJMS

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“…Many brain-enriched miRs have been identified and can be detected in body fluids, such as serum and plasma and cerebrospinal fluid, from PD patients (Nelson et al, 2008; Lu et al, 2017; Sheinerman et al, 2017). Dysregulated levels of miRs can be used for biomarkers of PD and are believed to participate in the etiology of PD (Lu et al, 2017; Ramaswamy et al, 2018; Roser et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Upregulated Expression of MicroRNA-204-5p Leads to the Death of Dopaminergic Cells by Targeting DYRK1A-Mediated Apoptotic Signaling Cascade

Chiu

Yeh

Chen

et al. 2019

Front. Cell. Neurosci.

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MicroRNAs (miRs) downregulate or upregulate the mRNA level by binding to the 3′-untranslated region (3′UTR) of target gene. Dysregulated miR levels can be used as biomarkers of Parkinson’s disease (PD) and could participate in the etiology of PD. In the present study, 45 brain-enriched miRs were evaluated in serum samples from 50 normal subjects and 50 sporadic PD patients. The level of miR-204-5p was upregulated in serum samples from PD patients. An upregulated level of miR-204-5p was also observed in the serum and substantia nigra (SN) of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Expression of miR-204-5p increased the level of α-synuclein (α-Syn), phosphorylated (phospho)-α-Syn, tau, or phospho-tau protein and resulted in the activation of endoplasmic reticulum (ER) stress in SH-SY5Y dopaminergic cells. Expression of miR-204-5p caused autophagy impairment and activation of c-Jun N-terminal kinase (JNK)-mediated apoptotic cascade in SH-SY5Y dopaminergic cells. Our study using the bioinformatic method and dual-luciferase reporter analysis suggests that miR-204-5p positively regulates mRNA expression of dual-specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) by directly interacting with 3′UTR of DYRK1A. The mRNA and protein levels of DYRK1A were increased in SH-SY5Y dopaminergic cells expressing miR-204-5p and SN of MPTP-induced PD mouse model. Knockdown of DYRK1A expression or treatment of the DYRK1A inhibitor harmine attenuated miR-204-5p-induced increase in protein expression of phospho-α-Syn or phospho-tau, ER stress, autophagy impairment, and activation of JNK-mediated apoptotic pathway in SH-SY5Y dopaminergic cells or primary cultured dopaminergic neurons. Our results suggest that upregulated expression of miR-204-5p leads to the death of dopaminergic cells by targeting DYRK1A-mediated ER stress and apoptotic signaling cascade.

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“…[ 2 5 8 ] Sustained efforts have been made to develop reliable biomarkers to aid their accurate diagnoses. [ 2 9 10 11 12 13 14 15 ]…”

Section: Introductionmentioning

confidence: 99%

Blood neurofilament light chain in Parkinson disease and atypical parkinsonisms

Wang

Shi³

et al. 2020

Medicine

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Background: Neurofilament light chain (NfL), an index of neuroaxonal injury, is a promising diagnostic and prognostic fluid biomarker with high translational value in many neurodegenerative disorders. Blood NfL measurement has been an exciting and active field of research in idiopathic Parkinson disease (PD) and atypical parkinsonisms. However, blood NfL levels in these parkinsonisms from existing literature were inconsistent. No comprehensive meta-analysis has ever been conducted. Methods: Three major biomedical electronic databases PubMed, Embase, and Web of Science were comprehensively searched from inception to July 10, 2020. This protocol will be prepared based on the guidelines recommended by the statement of Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P). Original observational studies that measured blood (serum/plasma) NfL concentrations in patients with parkinsonisms (multiple system atrophy [MSA], progressive supranuclear palsy [PSP], corticobasal syndrome [CBS], and dementia with Lewy bodies [DLB]), and healthy controls (HCs) will be included. Quality assessment of the included studies will be performed using the Newcastle Ottawa Scale (NOS). Meta-analyses will be conducted using the STATA software version 13.0. The standardized mean differences as the measure of effect size and 95% confidence intervals were calculated for each comparison of blood NfL levels. Heterogeneity analysis, sensitivity analysis, publication bias, subgroup analysis, and meta-regression analysis will be carried out to test the robustness of the results. Results: The meta-analysis will obtain the effect sizes of blood NfL levels in the following comparisons: PD versus HC, MSA versus HC, PSP versus HC, CBS versus HC, DLB versus HC, MSA versus PD, PSP versus PD, CBS versus PD, and DLB versus PD. Conclusions: The present meta-analysis will provide the quantitative evidence of NfL levels in idiopathic PD and atypical parkinsonisms, hoping to facilitate differential diagnoses in clinical practice. Registration number: INPLASY202070091.

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MicroRNAs to differentiate Parkinsonian disorders: Advances in biomarkers and therapeutics

Cited by 20 publications

References 146 publications

Protein Deimination Signatures in Plasma and Plasma-EVs and Protein Deimination in the Brain Vasculature in a Rat Model of Pre-Motor Parkinson’s Disease

Protein Deimination Signatures in Plasma and Plasma-EVs and Protein Deimination in the Brain Vasculature in a Rat Model of Pre-Motor Parkinson’s Disease

Upregulated Expression of MicroRNA-204-5p Leads to the Death of Dopaminergic Cells by Targeting DYRK1A-Mediated Apoptotic Signaling Cascade

Blood neurofilament light chain in Parkinson disease and atypical parkinsonisms

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