Deregulation of ncRNA in Neurodegenerative Disease: Focus on circRNA, lncRNA and miRNA in Amyotrophic Lateral Sclerosis

Ruffo, Paola; Strafella, Claudia; Cascella, Raffaella; Caputo, Valerio; Conforti, Francesca Luisa; Andò, Sebastiano; Giardina, Emiliano

doi:10.3389/fgene.2021.784996

Cited by 19 publications

(13 citation statements)

References 76 publications

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“…In addition to their physiological roles in skeletal muscle, circRNAs are being recognized as potential biomarkers in diseases of the nervous system, including ALS, Alzheimer’s disease, and other non-neurological diseases like lupus, diabetes, and glioblastoma [ 27 , 35 ]. Recently, circSMOX RNA was identified as a biomarker in the SOD1 G93A mouse with potential for tracking disease progression and other clinical features [ 36 ].…”

Section: Introductionmentioning

confidence: 99%

Transcriptomic analysis of human ALS skeletal muscle reveals a disease-specific pattern of dysregulated circRNAs

Tsitsipatis

Mazan-Mamczarz

et al. 2022

Aging

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Circular RNAs are abundant, covalently closed transcripts that arise in cells through back-splicing and display distinct expression patterns across cells and developmental stages. While their functions are largely unknown, their intrinsic stability has made them valuable biomarkers in many diseases. Here, we set out to examine circRNA patterns in amyotrophic lateral sclerosis (ALS). By RNA-sequencing analysis, we first identified circRNAs and linear RNAs that were differentially abundant in skeletal muscle biopsies from ALS compared to normal individuals. By RT-qPCR analysis, we confirmed that 8 circRNAs were significantly elevated and 10 were significantly reduced in ALS, while the linear mRNA counterparts, arising from shared precursor RNAs, generally did not change. Several of these circRNAs were also differentially abundant in motor neurons derived from human induced pluripotent stem cells (iPSCs) bearing ALS mutations, and across different disease stages in skeletal muscle from a mouse model of ALS (SOD1 G93A ). Interestingly, a subset of the circRNAs significantly elevated in ALS muscle biopsies were significantly reduced in the spinal cord samples from ALS patients and ALS (SOD1 G93A ) mice. In sum, we have identified differentially abundant circRNAs in ALS-relevant tissues (muscle and spinal cord) that could inform about neuromuscular molecular programs in ALS and guide the development of therapies.

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Section: Introductionmentioning

confidence: 99%

Transcriptomic analysis of human ALS skeletal muscle reveals a disease-specific pattern of dysregulated circRNAs

Tsitsipatis

Mazan-Mamczarz

et al. 2022

Aging

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“…Although important research progress has been made, the etiopathology of ALS is mostly unknown. The mechanisms underlying the development of the disease are multiple, with the involvement of a complex interaction between genetic and molecular characteristics [ 6 ]. The major ALS-related genes include superoxide dismutase 1 ( SOD1), FUSed in sarcoma (FUS) , TAR DNA binding protein (TARDBP) and chromosome 9 open reading frame 72 ( C9Orf72) [ 7 , 8 ].…”

Section: Amyotrophic Lateral Sclerosismentioning

confidence: 99%

The Advent of Omics Sciences in Clinical Trials of Motor Neuron Diseases

Ruffo

Cavallaro

Conforti

2022

JPM

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The “omics revolution” has totally changed the scientific research approach and is contributing to the development of personalized therapies. In motor neuron diseases (MNDs), a set of complex, multifactorial, late-onset and chronic neurodegenerative diseases, the use of multi-omics approaches in clinical trials is providing new opportunities to stratify patients and develop target therapies. To show how omics science is gaining momentum in MNDs, in this work, we review the interventional clinical trials for MNDs based on the application of omics sciences. We analyze a total of 62 clinical trials listed in the ClinicalTrials database where different omics approaches have been applied in an initial phase, for diagnosis or patient selection, or in subsequent stages to cluster subjects, identify molecular signatures or evaluate drugs security or efficacy. The rise of omics sciences in clinical experimentation of MNDs is leading to an upheaval in their diagnosis and therapy that will require significant investments and means to ensure the correct and rapid evolution of personalized medicine.

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“…To date, despite ALS being known to be a multifactorial disease associated with genetic predisposition, environmental factors, and lifestyle, its causes are unclear. In 10% of cases, ALS is caused by a genetic mutation that can characterize several generations of the same family (familial ALS (fALS)) or the disease arises suddenly and without any known familial link (sporadic ALS (sALS)) [ 3 ]. The main genes directly associated with the onset of the disease and which account for almost 50% of fALS and 6% of sALS cases in the world are SOD1 , TARDBP , FUS , and C9orf72 [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

SOD-1 Variants in Amyotrophic Lateral Sclerosis: Systematic Re-Evaluation According to ACMG-AMP Guidelines

Ruffo

Perrone

Conforti

2022

Genes

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Amyotrophic lateral sclerosis (ALS) is the most common type of motor neuron disease whose causes are unclear. The first ALS gene associated with the autosomal dominant form of the disease was SOD1. This gene has a high rate of rare variants, and an appropriate classification is essential for a correct ALS diagnosis. In this study, we re-evaluated the classification of all previously reported SOD1 variants (n = 202) from ALSoD, project MinE, and in-house databases by applying the ACMG-AMP criteria to ALS. New bioinformatics analysis, frequency rating, and a thorough search for functional studies were performed. We also proposed adjusting criteria strength describing how to apply them to SOD1 variants. Most of the previously reported variants have been reclassified as likely pathogenic and pathogenic based on the modified weight of the PS3 criterion, highlighting how in vivo or in vitro functional studies are determining their interpretation and classification. Furthermore, this study reveals the concordance and discordance of annotations between open databases, indicating the need for expert review to adapt the study of variants to a specific disease. Indeed, in complex diseases, such as ALS, the oligogenic inheritance, the presence of genes that act as risk factors and the reduced penetration must be considered. Overall, the diagnosis of ALS remains clinical, and improving variant classification could support genetic data as diagnostic criteria.

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Deregulation of ncRNA in Neurodegenerative Disease: Focus on circRNA, lncRNA and miRNA in Amyotrophic Lateral Sclerosis

Cited by 19 publications

References 76 publications

Transcriptomic analysis of human ALS skeletal muscle reveals a disease-specific pattern of dysregulated circRNAs

Transcriptomic analysis of human ALS skeletal muscle reveals a disease-specific pattern of dysregulated circRNAs

The Advent of Omics Sciences in Clinical Trials of Motor Neuron Diseases

SOD-1 Variants in Amyotrophic Lateral Sclerosis: Systematic Re-Evaluation According to ACMG-AMP Guidelines

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