Circulating small RNA signatures differentiate accurately the subtypes of muscular dystrophies: small-RNA next-generation sequencing analytics and functional insights

Muscular dystrophies are a group of rare and severe inherited disorders mainly affecting the muscle tissue. Duchene Muscular Dystrophy, Myotonic Dystrophy types 1 and 2, Limb Girdle Muscular Dystrophy and Facioscapulohumeral Muscular Dystrophy are some of the members of this family of disorders. In addition to the current diagnostic tools, there is an increasing interest for the development of novel non-invasive biomarkers for the diagnosis and monitoring of these diseases. miRNAs are small RNA molecules characterized by high stability in blood thus making them ideal biomarker candidates for various diseases. In this study, we present the first genome-wide next-generation small RNA sequencing in serum samples of five different types of muscular dystrophy patients and healthy individuals. We identified many small RNAs including miRNAs, lncRNAs, tRNAs, snoRNAs and snRNAs, that differentially discriminate the muscular dystrophy patients from the healthy individuals. Further analysis of the identified miRNAs showed that some miRNAs can distinguish the muscular dystrophy patients from controls and other miRNAs are specific to the type of muscular dystrophy. Bioinformatics analysis of the target genes for the most significant miRNAs and the biological role of these genes revealed different pathways that the dysregulated miRNAs are involved in each type of muscular dystrophy investigated. In conclusion, this study shows unique signatures of small RNAs circulating in five types of muscular dystrophy patients and provides a useful resource for future studies for the development of miRNA biomarkers in muscular dystrophies and for their involvement in the pathogenesis of the disorders

The regulation and role of NDRG2 during catabolic stress in skeletal muscle

Outcomes of these studies demonstrated novel role and regulation of skeletal muscle growth regulator, NDRG2. NDRG2 is highly expressed in chronic and diseased muscle conditions, defining its physiological role and function is required to determine whether it has a therapeutic potential to treat muscle atrophy

Early downregulation of hsa-miR-144-3p in serum from drug-naïve Parkinson’s disease patients

Advanced age represents one of the major risk factors for Parkinson’s Disease. Recent biomedical studies posit a role for microRNAs, also known to be remodelled during ageing. However, the relationship between microRNA remodelling and ageing in Parkinson’s Disease, has not been fully elucidated. Therefore, the aim of the present study is to unravel the relevance of microRNAs as biomarkers of Parkinson’s Disease within the ageing framework. We employed Next Generation Sequencing to profile serum microRNAs from samples informative for Parkinson’s Disease (recently diagnosed, drug-naïve) and healthy ageing (centenarians) plus healthy controls, age-matched with Parkinson’s Disease patients. Potential microRNA candidates markers, emerging from the combination of differential expression and network analyses, were further validated in an independent cohort including both drug-naïve and advanced Parkinson’s Disease patients, and healthy siblings of Parkinson’s Disease patients at higher genetic risk for developing the disease. While we did not find evidences of microRNAs co-regulated in Parkinson’s Disease and ageing, we report that hsa-miR-144-3p is consistently down-regulated in early Parkinson’s Disease patients. Moreover, interestingly, functional analysis revealed that hsa-miR-144-3p is involved in the regulation of coagulation, a process known to be altered in Parkinson’s Disease. Our results consistently show the down-regulation of hsa-mir144-3p in early Parkinson’s Disease, robustly confirmed across a variety of analytical and experimental analyses. These promising results ask for further research to unveil the functional details of the involvement of hsa-mir144-3p in Parkinson’s Disease

Early downregulation of hsa-miR-144-3p in serum from drug-naïve Parkinson’s disease patients

open101siThis work was supported by the Horizon 2020 Framework Programme (Grant number 634821, PROPAG-AGING).Advanced age represents one of the major risk factors for Parkinson’s Disease. Recent biomedical studies posit a role for microRNAs, also known to be remodelled during ageing. However, the relationship between microRNA remodelling and ageing in Parkinson’s Disease, has not been fully elucidated. Therefore, the aim of the present study is to unravel the relevance of microRNAs as biomarkers of Parkinson’s Disease within the ageing framework. We employed Next Generation Sequencing to profile serum microRNAs from samples informative for Parkinson’s Disease (recently diagnosed, drug-naïve) and healthy ageing (centenarians) plus healthy controls, age-matched with Parkinson’s Disease patients. Potential microRNA candidates markers, emerging from the combination of differential expression and network analyses, were further validated in an independent cohort including both drug-naïve and advanced Parkinson’s Disease patients, and healthy siblings of Parkinson’s Disease patients at higher genetic risk for developing the disease. While we did not find evidences of microRNAs co-regulated in Parkinson’s Disease and ageing, we report that hsa-miR-144-3p is consistently down-regulated in early Parkinson’s Disease patients. Moreover, interestingly, functional analysis revealed that hsa-miR-144-3p is involved in the regulation of coagulation, a process known to be altered in Parkinson’s Disease. Our results consistently show the down-regulation of hsa-mir144-3p in early Parkinson’s Disease, robustly confirmed across a variety of analytical and experimental analyses. These promising results ask for further research to unveil the functional details of the involvement of hsa-mir144-3p in Parkinson’s Disease.openZago E.; Dal Molin A.; Dimitri G.M.; Xumerle L.; Pirazzini C.; Bacalini M.G.; Maturo M.G.; Azevedo T.; Spasov S.; Gomez-Garre P.; Perinan M.T.; Jesus S.; Baldelli L.; Sambati L.; Calandra Buonaura G.; Garagnani P.; Provini F.; Cortelli P.; Mir P.; Trenkwalder C.; Mollenhauer B.; Franceschi C.; Lio P.; Nardini C.; Adarmes-Gomez A.; Azevedo T.; Bacalini M.G.; Baldelli L.; Bartoletti-Stella A.; Bhatia K.P.; Marta B.-T.; Boninsegna C.; Broli M.; Dolores B.-R.; Calandra-Buonaura G.; Capellari S.; Carrion-Claro M.; Cilea R.; Clayton R.; Cortelli P.; Molin A.D.; De Luca S.; De Massis P.; Dimitri G.M.; Doykov I.; Escuela-Martin R.; Fabbri G.; Franceschi C.; Gabellini A.; Garagnani P.; Giuliani C.; Gomez-Garre P.; Guaraldi P.; Hagg S.; Hallqvist J.; Halsband C.; Heywood W.; Houlden H.; Huertas I.; Jesus S.; Jylhava J.; Labrador-Espinosa M.A.; Licari C.; Lio P.; Luchinat C.; Macias D.; Macri S.; Magrinelli F.; Rodriguez J.F.M.; Massimo D.; Maturo M.G.; Mengozzi G.; Meoni G.; Mignani F.; Milazzo M.; Mills K.; Mir P.; Mollenhauer B.; Nardini C.; Nassetti S.A.; Pedersen N.L.; Perinan-Tocino M.T.; Pirazzini C.; Provini F.; Ravaioli F.; Sala C.; Sambati L.; Scaglione C.L.M.; Schade S.; Schreglmann S.; Spasov S.; Strom S.; Tejera-Parrado C.; Tenori L.; Trenkwalder C.; Turano P.; Valzania F.; Ortega R.V.; Williams D.; Xumerle L.; Zago E.Zago E.; Dal Molin A.; Dimitri G.M.; Xumerle L.; Pirazzini C.; Bacalini M.G.; Maturo M.G.; Azevedo T.; Spasov S.; Gomez-Garre P.; Perinan M.T.; Jesus S.; Baldelli L.; Sambati L.; Calandra Buonaura G.; Garagnani P.; Provini F.; Cortelli P.; Mir P.; Trenkwalder C.; Mollenhauer B.; Franceschi C.; Lio P.; Nardini C.; Adarmes-Gomez A.; Azevedo T.; Bacalini M.G.; Baldelli L.; Bartoletti-Stella A.; Bhatia K.P.; Marta B.-T.; Boninsegna C.; Broli M.; Dolores B.-R.; Calandra-Buonaura G.; Capellari S.; Carrion-Claro M.; Cilea R.; Clayton R.; Cortelli P.; Molin A.D.; De Luca S.; De Massis P.; Dimitri G.M.; Doykov I.; Escuela-Martin R.; Fabbri G.; Franceschi C.; Gabellini A.; Garagnani P.; Giuliani C.; Gomez-Garre P.; Guaraldi P.; Hagg S.; Hallqvist J.; Halsband C.; Heywood W.; Houlden H.; Huertas I.; Jesus S.; Jylhava J.; Labrador-Espinosa M.A.; Licari C.; Lio P.; Luchinat C.; Macias D.; Macri S.; Magrinelli F.; Rodriguez J.F.M.; Massimo D.; Maturo M.G.; Mengozzi G.; Meoni G.; Mignani F.; Milazzo M.; Mills K.; Mir P.; Mollenhauer B.; Nardini C.; Nassetti S.A.; Pedersen N.L.; Perinan-Tocino M.T.; Pirazzini C.; Provini F.; Ravaioli F.; Sala C.; Sambati L.; Scaglione C.L.M.; Schade S.; Schreglmann S.; Spasov S.; Strom S.; Tejera-Parrado C.; Tenori L.; Trenkwalder C.; Turano P.; Valzania F.; Ortega R.V.; Williams D.; Xumerle L.; Zago E

Expression and Biological Functions of miRNAs in Chronic Pain: A Review on Human Studies

none10noChronic pain is a major public health problem and an economic burden worldwide. However, its underlying pathological mechanisms remain unclear. MicroRNAs (miRNAs) are a class of small noncoding RNAs that post-transcriptionally regulate gene expression and serve key roles in physiological and pathological processes. This review aims to synthesize the human studies examining miRNA expression in the pathogenesis of chronic primary pain and chronic secondary pain. Additionally, to understand the potential pathophysiological impact of miRNAs in these conditions, an in silico analysis was performed to reveal the target genes and pathways involved in primary and secondary pain and their differential regulation in the different types of chronic pain. The findings, methodological issues and challenges of miRNA research in the pathophysiology of chronic pain are discussed. The available evidence suggests the potential role of miRNA in disease pathogenesis and possibly the pain process, eventually enabling this role to be exploited for pain monitoring and management.Sabina S.; Panico A.; Mincarone P.; Leo C.G.; Garbarino S.; Grassi T.; Bagordo F.; De Donno A.; Scoditti E.; Tumolo M.R.Sabina, S.; Panico, A.; Mincarone, P.; Leo, C. G.; Garbarino, S.; Grassi, T.; Bagordo, F.; De Donno, A.; Scoditti, E.; Tumolo, M. R

Downregulation of exosomal miR-204-5p and miR-632 as a biomarker for FTD: a GENFI study

OBJECTIVE: To determine whether exosomal microRNAs (miRNAs) in cerebrospinal fluid (CSF) of patients with frontotemporal dementia (FTD) can serve as diagnostic biomarkers, we assessed miRNA expression in the Genetic Frontotemporal Dementia Initiative (GENFI) cohort and in sporadic FTD. METHODS: GENFI participants were either carriers of a pathogenic mutation in progranulin, chromosome 9 open reading frame 72 or microtubule-associated protein tau or were at risk of carrying a mutation because a first-degree relative was a known symptomatic mutation carrier. Exosomes were isolated from CSF of 23 presymptomatic and 15 symptomatic mutation carriers and 11 healthy non-mutation carriers. Expression of 752 miRNAs was measured using quantitative PCR (qPCR) arrays and validated by qPCR using individual primers. MiRNAs found differentially expressed in symptomatic compared with presymptomatic mutation carriers were further evaluated in a cohort of 17 patients with sporadic FTD, 13 patients with sporadic Alzheimer's disease (AD) and 10 healthy controls (HCs) of similar age. RESULTS: In the GENFI cohort, miR-204-5p and miR-632 were significantly decreased in symptomatic compared with presymptomatic mutation carriers. Decrease of miR-204-5p and miR-632 revealed receiver operator characteristics with an area of 0.89 (90% CI 0.79 to 0.98) and 0.81 (90% CI 0.68 to 0.93), respectively, and when combined an area of 0.93 (90% CI 0.87 to 0.99). In sporadic FTD, only miR-632 was significantly decreased compared with AD and HCs. Decrease of miR-632 revealed an area of 0.90 (90% CI 0.81 to 0.98). CONCLUSIONS: Exosomal miR-204-5p and miR-632 have potential as diagnostic biomarkers for genetic FTD and miR-632 also for sporadic FTD

Mammalian microRNAs: a small world for fine-tuning gene expression

The basis of eukaryotic complexity is an intricate genetic architecture where parallel systems are involved in tuning gene expression, via RNA-DNA, RNA-RNA, RNA-protein, and DNA-protein interactions. In higher organisms, about 97% of the transcriptional output is represented by noncoding RNA (ncRNA) encompassing not only rRNA, tRNA, introns, 5′ and 3′ untranslated regions, transposable elements, and intergenic regions, but also a large, rapidly emerging family named microRNAs. MicroRNAs are short 20-22-nucleotide RNA molecules that have been shown to regulate the expression of other genes in a variety of eukaryotic systems. MicroRNAs are formed from larger transcripts that fold to produce hairpin structures and serve as substrates for the cytoplasmic Dicer, a member of the RNase III enzyme family. A recent analysis of the genomic location of human microRNA genes suggested that 50% of microRNA genes are located in cancer-associated genomic regions or in fragile sites. This review focuses on the possible implications of microRNAs in post-transcriptional gene regulation in mammalian diseases, with particular focus on cancer. We argue that developing mouse models for deleted and/or overexpressed microRNAs will be of invaluable interest to decipher the regulatory networks where microRNAs are involved

Downregulation of exosomal miR-204-5p and miR-632 as a biomarker for FTD: A GENFI study

Objective: To determine whether exosomal microRNAs (miRNAs) in cerebrospinal fluid (CSF) of patients with frontotemporal dementia (FTD) can serve as diagnostic biomarkers, we assessed miRNA expression in the Genetic Frontotemporal Dementia Initiative (GENFI) cohort and in sporadic FTD. Methods: GENFI participants were either carriers of a pathogenic mutation in progranulin, chromosome 9 open reading frame 72 or microtubule-associated protein tau or were at risk of carrying a mutation because a first-degree relative was a known symptomatic mutation carrier. Exosomes were isolated from CSF of 23 presymptomatic and 15 symptomatic mutation carriers and 11 healthy non-mutation carriers. Expression of 752 miRNAs was measured using quantitative PCR (qPCR) arrays and validated by qPCR using individual primers. MiRNAs found differentially expressed in symptomatic compared with presymptomatic mutation carriers were further evaluated in a cohort of 17 patients with sporadic FTD, 13 patients with sporadic Alzheimer's disease (AD) and 10 healthy controls (HCs) of similar age. Results: In the GENFI cohort, miR-204-5p and miR-632 were significantly decreased in symptomatic compared with presymptomatic mutation carriers. Decrease of miR-204-5p and miR-632 revealed receiver operator characteristics with an area of 0.89 (90% CI 0.79 to 0.98) and 0.81 (90% CI 0.68 to 0.93), respectively, and when combined an area of 0.93 (90% CI 0.87 to 0.99). In sporadic FTD, only miR-632 was significantly decreased compared with AD and HCs. Decrease of miR-632 revealed an area of 0.90 (90% CI 0.81 to 0.98). Conclusions: Exosomal miR-204-5p and miR-632 have potential as diagnostic biomarkers for genetic FTD and miR-632 also for sporadic FTD

Downregulation of exosomal miR-204-5p and miR-632 as a biomarker for FTD: a GENFI study.

OBJECTIVE: To determine whether exosomal microRNAs (miRNAs) in cerebrospinal fluid (CSF) of patients with frontotemporal dementia (FTD) can serve as diagnostic biomarkers, we assessed miRNA expression in the Genetic Frontotemporal Dementia Initiative (GENFI) cohort and in sporadic FTD. METHODS: GENFI participants were either carriers of a pathogenic mutation in progranulin, chromosome 9 open reading frame 72 or microtubule-associated protein tau or were at risk of carrying a mutation because a first-degree relative was a known symptomatic mutation carrier. Exosomes were isolated from CSF of 23 presymptomatic and 15 symptomatic mutation carriers and 11 healthy non-mutation carriers. Expression of 752 miRNAs was measured using quantitative PCR (qPCR) arrays and validated by qPCR using individual primers. MiRNAs found differentially expressed in symptomatic compared with presymptomatic mutation carriers were further evaluated in a cohort of 17 patients with sporadic FTD, 13 patients with sporadic Alzheimer's disease (AD) and 10 healthy controls (HCs) of similar age. RESULTS: In the GENFI cohort, miR-204-5p and miR-632 were significantly decreased in symptomatic compared with presymptomatic mutation carriers. Decrease of miR-204-5p and miR-632 revealed receiver operator characteristics with an area of 0.89 (90% CI 0.79 to 0.98) and 0.81 (90% CI 0.68 to 0.93), respectively, and when combined an area of 0.93 (90% CI 0.87 to 0.99). In sporadic FTD, only miR-632 was significantly decreased compared with AD and HCs. Decrease of miR-632 revealed an area of 0.90 (90% CI 0.81 to 0.98). CONCLUSIONS: Exosomal miR-204-5p and miR-632 have potential as diagnostic biomarkers for genetic FTD and miR-632 also for sporadic FTD