Specific Signatures of Serum miRNAs as Potential Biomarkers to Discriminate Clinically Similar Neurodegenerative and Vascular-Related Diseases

Barbagallo, Cristina; Mostile, Giovanni; Baglieri, Gloriangela; Giunta, Flavia; Luca, Antonina; Raciti, Loredana; Zappia, Mario; Purrello, Michele; Ragusa, Marco; Nicoletti, Alessandra

doi:10.1007/s10571-019-00751-y

Cited by 104 publications

(78 citation statements)

References 59 publications

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“…We also observed a systematic decline in miRNA expression over time, revealing a signature of miRNAs associated with leukocytes, in particular monocytes and B cells, as well as exosomes and RBCs. Among these are several members of the miR-19 and miR-29 families that are consistent with earlier findings [33][34][35][36][37] . Also, PD induced changes for both monocyte and exosome expression signatures has been reported in several other studies [38][39][40][41] .…”

Section: Discussionsupporting

confidence: 91%

Deep sncRNA-seq of the PPMI cohort to study Parkinson’s disease progression

Kern

Fehlmann

Violich

et al. 2020

Preprint

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Coding and non-coding RNAs have diagnostic and prognostic importance in Parkinson's diseases (PD). We studied circulating small non-coding RNAs (sncRNAs) in 7, 003 samples from two longitudinal PD cohorts (Parkinson's Progression Marker Initiative (PPMI) and Luxembourg Parkinson's Study (NCER-PD)) and modelled their influence on the transcriptome. First, we sequenced sncRNAs in 5, 450 blood samples of 1, 614 individuals in PPMI. The majority of 323 billion reads (59 million reads per sample) mapped to miRNAs. Other covered RNA classes include piRNAs, rRNAs, snoRNAs, tRNAs, scaRNAs, and snRNAs. De-regulated miRNAs were associated with the disease and disease progression and occur in two distinct waves in the third and seventh decade of live. Originating mostly from a characteristic set of immune cells they resemble a systemic inflammation response and mitochondrial dysfunction, two hallmarks of PD. By profiling 1, 553 samples from 1, 024 individuals in the NCER-PD cohort using an independent technology, we validate relevant findings from the sequencing study. Finally, network analysis of sncRNAs and transcriptome sequencing of the original cohort identified regulatory modules emerging in progressing PD patients.miRNA studies to date, covering over 3, 000 patients and controls 21 .Advanced biomarker studies however require carefully designed cohorts. Already a few large-scale PD studies aiming to advance diagnosis, prognosis and therapeutics fulfil respective requirements 22-24 . Among them, the Parkinson's Progression Marker Initiative (PPMI) is a multi-cohort, longitudinal observational study designed to discover and validate objective biomarkers of Parkinson's 25 . The PPMI project constitutes a global effort of 33 clinical sites in 11 countries with regular study participant assessments (Figure 1a). It also features comprehensive clinical phenotyping to observe hundreds of characteristics of the known subtypes of the disease, such as the idiopathic and genetic forms. Further, longitudinal biosampling following rigorous Standard Operating Procedures (SOPs) is performed to set a framework for the discovery and validation of early-onset and prognostic biomarkers. To identify potential non-coding RNA and transcriptomic markers in PPMI we performed RNA-seq on blood samples drawn at each clinical visit. For short and long RNAs, we carried out optimized assays and sequenced separate aliquots from the same blood samples for paired RNA analyses. Here, we present the evaluation of the sncRNA-seq fraction for disease detection and progression tracking. We examine the potential of different classes of small RNAs but emphasise the role of miRNAs. We also validate relevant findings for miRNAs on the Luxembourg Parkinson's Study in the framework of the National Centre for Excellence in Research on PD (NCER-PD) cohort 22 , which was performed independently and with a different technology. Finally, we provide insights on how the key non-coding RNAs regulate gene expression by utilizing the long RNA sequencing data. Specific ana...

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Section: Discussionsupporting

confidence: 91%

Deep sncRNA-seq of the PPMI cohort to study Parkinson’s disease progression

Kern

Fehlmann

Violich

et al. 2020

Preprint

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“…In contrast, the miR-505 expression result diminished in PD patients, thus, these two ex-miRNAs may be valuable for the early diagnosis of PD [ 137 ]. In another study, the ex-miRNA content of the PD patients serum was compared with healthy individuals and, notably, the expression of ex-miR-22, ex-miR-23a, ex-miR-24, ex-miR-142-3p and ex-miR-222 was considerably higher in the serum of PD patients [ 138 ]. Ravanidis et al [ 108 ] applied a specially designed panel of miRNAs to evaluate the miRNA profile of genetic and idiopathic PD patients with healthy individuals.…”

Section: Mirna Dysregulation and Mitochondrial Dysfunction In Alzhmentioning

confidence: 99%

MicroRNAs Dysregulation and Mitochondrial Dysfunction in Neurodegenerative Diseases

Catanesi

d’Angelo

Tupone

et al. 2020

IJMS

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Neurodegenerative diseases are debilitating and currently incurable conditions causing severe cognitive and motor impairments, defined by the progressive deterioration of neuronal structure and function, eventually causing neuronal loss. Understand the molecular and cellular mechanisms underlying these disorders are essential to develop therapeutic approaches. MicroRNAs (miRNAs) are short non-coding RNAs implicated in gene expression regulation at the post-transcriptional level. Moreover, miRNAs are crucial for different processes, including cell growth, signal transmission, apoptosis, cancer and aging-related neurodegenerative diseases. Altered miRNAs levels have been associated with the formation of reactive oxygen species (ROS) and mitochondrial dysfunction. Mitochondrial dysfunction and ROS formation occur in many neurodegenerative diseases such as Alzheimer’s, Parkinson’s and Huntington’s diseases. The crosstalk existing among oxidative stress, mitochondrial dysfunction and miRNAs dysregulation plays a pivotal role in the onset and progression of neurodegenerative diseases. Based on this evidence, in this review, with a focus on miRNAs and their role in mitochondrial dysfunction in aging-related neurodegenerative diseases, with a focus on their potential as diagnostic biomarkers and therapeutic targets.

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“…However, several reports showed promising results that have not been confirmed in independent studies [ 7 ]. The application of circulating RNA molecules, including non-coding RNAs (ncRNAs), as biomarkers has been widely explored in the last few decades; miRNAs have been suggested as diagnostic biomarkers for several diseases, including neurodegenerative [ 8 , 9 ], neurodevelopmental [ 10 ], traumatic [ 11 ], neoplastic [ 12 , 13 ], and metabolic conditions [ 14 , 15 ]. Indeed, miRNAs have been detected in all analyzed biological fluids [ 16 , 17 , 18 ], making them useful as disease biomarkers measurable in all body districts.…”

Section: Introductionmentioning

confidence: 99%

Uncharacterized RNAs in Plasma of Alzheimer’s Patients Are Associated with Cognitive Impairment and Show a Potential Diagnostic Power

Barbagallo

Martino

Grasso

et al. 2020

IJMS

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Alzheimer’s disease (AD) diagnosis is actually based on clinical evaluation and brain-imaging tests, and it can often be confirmed only post-mortem. Therefore, new non-invasive molecular biomarkers are necessary to improve AD diagnosis. As circulating microRNA biomarkers have been proposed for many diseases, including AD, we aimed to identify new diagnostic non-small RNAs in AD. Whole transcriptome analysis was performed on plasma samples of five AD and five unaffected individuals (CTRL) using the Clariom D Pico Assay, followed by validation in real-time PCR on 37 AD patients and 37 CTRL. Six differentially expressed (DE) transcripts were identified: GS1-304P7.3 (upregulated), NONHSAT090268, TC0100011037, TC0400008478, TC1400008125, and UBE2V1 (downregulated). Peripheral blood mononuclear cells (PBMCs) may influence the expression of circulating RNAs and their analysis has been proposed to improve AD clinical management. Accordingly, DE transcript expression was also evaluated in PBMCs, showing no difference between AD and CTRL. ROC (receiver operating characteristic) curve analysis was performed to evaluate the diagnostic accuracy of each DE transcript and a signature including all of them. A correlation between cognitive impairment and GS1-304P7.3, NONHSAT090268, TC0100011037, and TC0400008478 was detected, suggesting a potential association between their extracellular abundance and AD clinical phenotype. Finally, this study identified six transcripts showing altered expression in the plasma of AD patients. Given the need for new, accurate blood biomarkers for AD diagnosis, these transcripts may be considered for further analyses in larger cohorts, also in combination with other biomarkers, aiming to identify specific RNA-based biomarkers to be eventually applied to clinical practice.

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Specific Signatures of Serum miRNAs as Potential Biomarkers to Discriminate Clinically Similar Neurodegenerative and Vascular-Related Diseases

Cited by 104 publications

References 59 publications

Deep sncRNA-seq of the PPMI cohort to study Parkinson’s disease progression

Deep sncRNA-seq of the PPMI cohort to study Parkinson’s disease progression

MicroRNAs Dysregulation and Mitochondrial Dysfunction in Neurodegenerative Diseases

Uncharacterized RNAs in Plasma of Alzheimer’s Patients Are Associated with Cognitive Impairment and Show a Potential Diagnostic Power

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