Insights into the identification of a molecular signature for amyotrophic lateral sclerosis exploiting integrated microRNA profiling of iPSC-derived motor neurons and exosomes

Melzi, Valentina; Gagliardi, Delia; Resnati, Davide; Meneri, Megi; Dioni, Laura; Masrori, Pegah; Hersmus, Nicole; Poesen, Koen; Locatelli, Martina; Biella, Fabio; Silipigni, Rosamaria; Bollati, Valentina; Bresolin, Nereo; Comi, Giacomo Pietro; Damme, Philip Van; Nizzardo, Monica; Rizzuti, Mafalda

doi:10.1007/s00018-022-04217-1

Cited by 16 publications

(28 citation statements)

References 75 publications

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“…The expression of the above-listed miRNAs was also checked in the CSF of patients with familial and sporadic ALS, and dysregulation of miR-34a-3p and miR-625-3p levels was observed. 163 Identifying the exact mechanism via which these identified miRNAs regulate the disease could help design better therapies in the future. One of the aspects of ALS therapies utilizes stem-cell-based approaches.…”

Section: Huntington's Diseasementioning

confidence: 99%

Smart Nanoscale Extracellular Vesicles in the Brain: Unveiling their Biology, Diagnostic Potential, and Therapeutic Applications

Onkar,

Khan,

Goenka

et al. 2024

ACS Appl. Mater. Interfaces

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Information exchange is essential for the brain, where it communicates the physiological and pathological signals to the periphery and vice versa. Extracellular vesicles (EVs) are a heterogeneous group of membrane-bound cellular informants actively transferring informative calls to and from the brain via lipids, proteins, and nucleic acid cargos. In recent years, EVs have also been widely used to understand brain function, given their "cell-like" properties. On the one hand, the presence of neuron and astrocyte-derived EVs in biological fluids have been exploited as biomarkers to understand the mechanisms and progression of multiple neurological disorders; on the other, EVs have been used in designing targeted therapies due to their potential to cross the blood-brain-barrier (BBB). Despite the expanding literature on EVs in the context of central nervous system (CNS) physiology and related disorders, a comprehensive compilation of the existing knowledge still needs to be made available. In the current review, we provide a detailed insight into the multifaceted role of brain-derived extracellular vesicles (BDEVs) in the intricate regulation of brain physiology. Our focus extends to the significance of these EVs in a spectrum of disorders, including brain tumors, neurodegenerative conditions, neuropsychiatric diseases, autoimmune disorders, and others. Throughout the review, parallels are drawn for using EVs as biomarkers for various disorders, evaluating their utility in early detection and monitoring. Additionally, we discuss the promising prospects of utilizing EVs in targeted therapy while acknowledging the existing limitations and challenges associated with their applications in clinical scenarios. A foundational comprehension of the current state-of-the-art in EV research is essential for informing the design of future studies.

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Section: Huntington's Diseasementioning

confidence: 99%

Smart Nanoscale Extracellular Vesicles in the Brain: Unveiling their Biology, Diagnostic Potential, and Therapeutic Applications

Onkar,

Khan,

Goenka

et al. 2024

ACS Appl. Mater. Interfaces

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“…miR‐34a and miR‐335 increased ROS production and impaired mitochondrial antioxidant function. Similarly, miR‐625‐3p targets lncRNA‐p21 and mediates neuroinflammation, oxidative stress, and apoptosis 243 . Nucleolar complex protein 2 homologs (NOC2L) are overexpressed in CSF exosomes of patients with sporadic ALS.…”

Section: Exosomes In Neuropsychiatric Disordersmentioning

confidence: 99%

Exosomes in brain diseases: Pathogenesis and therapeutic targets

Pang

et al. 2023

MedComm

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Exosomes are extracellular vesicles with diameters of about 100 nm that are naturally secreted by cells into body fluids. They are derived from endosomes and are wrapped in lipid membranes. Exosomes are involved in intracellular metabolism and intercellular communication. They contain nucleic acids, proteins, lipids, and metabolites from the cell microenvironment and cytoplasm. The contents of exosomes can reflect their cells’ origin and allow the observation of tissue changes and cell states under disease conditions. Naturally derived exosomes have specific biomolecules that act as the “fingerprint” of the parent cells, and the contents changed under pathological conditions can be used as biomarkers for disease diagnosis. Exosomes have low immunogenicity, are small in size, and can cross the blood–brain barrier. These characteristics make exosomes unique as engineering carriers. They can incorporate therapeutic drugs and achieve targeted drug delivery. Exosomes as carriers for targeted disease therapy are still in their infancy, but exosome engineering provides a new perspective for cell‐free disease therapy. This review discussed exosomes and their relationship with the occurrence and treatment of some neuropsychiatric diseases. In addition, future applications of exosomes in the diagnosis and treatment of neuropsychiatric disorders were evaluated in this review.

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“…In PD, this miRNA was enriched in small EVs and associated with disease duration and clinical characteristics (Grossi et al, 2021). Hsa-miR-34a was also associated with disease relapse in MS (Ghadiri et al, 2018) and disease duration in ALS (Raheja et al, 2018), while upregulation in CSF of ALS patients was also observed (Rizzuti et al, 2022). It was proposed as a negative regulator of C9ORF72, a gene commonly mutated in familial ALS (Kmetzsch et al, 2021).…”

Section: Hsa-mir-34amentioning

confidence: 99%

Shared miRNA landscapes of COVID-19 and neurodegeneration confirm neuroinflammation as an important overlapping feature

Trampuž

Vogrinc

Goričar

et al. 2023

Front. Mol. Neurosci.

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IntroductionDevelopment and worsening of most common neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis, have been associated with COVID-19 However, the mechanisms associated with neurological symptoms in COVID-19 patients and neurodegenerative sequelae are not clear. The interplay between gene expression and metabolite production in CNS is driven by miRNAs. These small non-coding molecules are dysregulated in most common neurodegenerative diseases and COVID-19.MethodsWe have performed a thorough literature screening and database mining to search for shared miRNA landscapes of SARS-CoV-2 infection and neurodegeneration. Differentially expressed miRNAs in COVID-19 patients were searched using PubMed, while differentially expressed miRNAs in patients with five most common neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and multiple sclerosis) were searched using the Human microRNA Disease Database. Target genes of the overlapping miRNAs, identified with the miRTarBase, were used for the pathway enrichment analysis performed with Kyoto Encyclopedia of Genes and Genomes and Reactome.ResultsIn total, 98 common miRNAs were found. Additionally, two of them (hsa-miR-34a and hsa-miR-132) were highlighted as promising biomarkers of neurodegeneration, as they are dysregulated in all five most common neurodegenerative diseases and COVID-19. Additionally, hsa-miR-155 was upregulated in four COVID-19 studies and found to be dysregulated in neurodegeneration processes as well. Screening for miRNA targets identified 746 unique genes with strong evidence for interaction. Target enrichment analysis highlighted most significant KEGG and Reactome pathways being involved in signaling, cancer, transcription and infection. However, the more specific identified pathways confirmed neuroinflammation as being the most important shared feature.DiscussionOur pathway based approach has identified overlapping miRNAs in COVID-19 and neurodegenerative diseases that may have a valuable potential for neurodegeneration prediction in COVID-19 patients. Additionally, identified miRNAs can be further explored as potential drug targets or agents to modify signaling in shared pathways.Graphical AbstractShared miRNA molecules among the five investigated neurodegenerative diseases and COVID-19 were identified. The two overlapping miRNAs, hsa-miR-34a and has-miR-132, present potential biomarkers of neurodegenerative sequelae after COVID-19. Furthermore, 98 common miRNAs between all five neurodegenerative diseases together and COVID-19 were identified. A KEGG and Reactome pathway enrichment analyses was performed on the list of shared miRNA target genes and finally top 20 pathways were evaluated for their potential for identification of new drug targets. A common feature of identified overlapping miRNAs and pathways is neuroinflammation. AD, Alzheimer’s disease; ALS, amyotrophic lateral sclerosis; COVID-19, coronavirus disease 2019; HD, Huntington’s disease; KEGG, Kyoto Encyclopedia of Genes and Genomes; MS, multiple sclerosis; PD, Parkinson’s disease.

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Insights into the identification of a molecular signature for amyotrophic lateral sclerosis exploiting integrated microRNA profiling of iPSC-derived motor neurons and exosomes

Cited by 16 publications

References 75 publications

Smart Nanoscale Extracellular Vesicles in the Brain: Unveiling their Biology, Diagnostic Potential, and Therapeutic Applications

Smart Nanoscale Extracellular Vesicles in the Brain: Unveiling their Biology, Diagnostic Potential, and Therapeutic Applications

Exosomes in brain diseases: Pathogenesis and therapeutic targets

Shared miRNA landscapes of COVID-19 and neurodegeneration confirm neuroinflammation as an important overlapping feature

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