circRNA Regulates Dopaminergic Synapse, MAPK, and Long-term Depression Pathways in Huntington Disease

Marfil-Marin, Ernesto; Santamaría‐Olmedo, Mónica; PerezGrovas‐Saltijeral, Adriana; Valdés-Flores, Margarita; Ochoa-Morales, Adriana; Jara‐Prado, Aurelio; Sevilla‐Montoya, Rosalba; Camacho‐Molina, Alejandra; Hidalgo‐Bravo, Alberto

doi:10.1007/s12035-021-02536-1

Cited by 8 publications

(11 citation statements)

References 37 publications

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“…Finally, circRNAs also represent a new category of promising RNA biomarkers. A recent study detected 23 dysregulated circRNAs in a murine cell line, having functions associated with the dopaminergic synapse [ 74 ], while our work, shows dysregulation of circRNAs in neuronal progenitors expressing aberrantly long Htt CAG repeat [ 75 ]. CircRNA detection and dysregulation in the human blood samples from HD patients remains a still unexplored research area.…”

Section: Rna: a New Potential Class Of Biomarkersmentioning

confidence: 57%

“…Recently, 23 circRNAs were found to be dysregulated in an HD murine model, overexpressing mutant huntingtin fragment. Their function was associated with dopaminergic synapses, MAPK and long-term depression, all of which were previously related to HD pathogenesis [ 74 ]. On the other hand, our genome-wide analyses using mouse knock-in neuronal progenitors series clearly demonstrated a reduction in more than 500 circRNAs following the expression of the expanded CAG alleles [ 75 ].…”

Section: Rna: a New Potential Class Of Biomarkersmentioning

confidence: 99%

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Current Diagnostic Methods and Non-Coding RNAs as Possible Biomarkers in Huntington’s Disease

Pellegrini

Bergonzoni

Perrone

et al. 2022

Genes

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Whether as a cause or a symptom, RNA transcription is recurrently altered in pathologic conditions. This is also true for non-coding RNAs, with regulatory functions in a variety of processes such as differentiation, cell identity and metabolism. In line with their increasingly recognized roles in cellular pathways, RNAs are also currently evaluated as possible disease biomarkers. They could be informative not only to follow disease progression and assess treatment efficacy in clinics, but also to aid in the development of new therapeutic approaches. This is especially important for neurological and genetic disorders, where the administration of appropriate treatment during the disease prodromal stage could significantly delay, if not halt, disease progression. In this review we focus on the current status of biomarkers in Huntington’s Disease (HD), a fatal hereditary and degenerative disease condition. First, we revise the sources and type of wet biomarkers currently in use. Then, we explore the feasibility of different RNA types (miRNA, ncRNA, circRNA) as possible biomarker candidates, discussing potential advantages, disadvantages, sources of origin and the ongoing investigations on this topic.

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Section: Rna: a New Potential Class Of Biomarkersmentioning

confidence: 57%

Section: Rna: a New Potential Class Of Biomarkersmentioning

confidence: 99%

Current Diagnostic Methods and Non-Coding RNAs as Possible Biomarkers in Huntington’s Disease

Pellegrini

Bergonzoni

Perrone

et al. 2022

Genes

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“…For example, circRNA microarray profiling performed in a rat PC12-Q74 cell line identified 23 circRNAs as differentially expressed. Strikingly, 16 of the 19 downregulated circRNAs represent circRERE isoforms (Marfil-Marin et al ., 2021). HD is also characterised by alterations in dopaminergic neurotransmission, which is perturbed in miR-128-3p deficient mice (Tan et al ., 2013), thereby providing a link between circRERE and miR-128-3p.…”

Section: Discussionmentioning

confidence: 99%

“…circHomer1 is downregulated in the prefrontal cortex of bipolar disorder and schizophrenia patients, and knockdown of circHomer1 in the mouse orbitofrontal cortex results in deficits in cognitive flexibility (Zimmerman et al ., 2020). Furthermore, circRNAs are differentially expressed in pre- and post-symptomatic Alzheimer’s (Dube et al, 2019) and Huntington’s disease (Marfil-Marin et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

A functional screen uncovers circular RNAs regulating excitatory synaptogenesis in hippocampal neurons

Kelly,

Bicker,

Winterer

et al. 2024

Preprint

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Circular RNAs (circRNAs) are an expanding class of largely unexplored RNAs which are prominently enriched in the mammalian brain. Here, we systematically interrogated their role in excitatory synaptogenesis of rat hippocampal neurons using RNA interference. Thereby, we identified seven circRNAs as negative regulators of excitatory synapse formation, many of which contain high-affinity microRNA binding sites. Knockdown of one of these candidates, circRERE, surprisingly promoted the formation of electrophysiologically silent synapses. Mechanistically, circRERE knockdown resulted in a preferential upregulation of synaptic mRNAs containing binding sites for miR-128-3p because of a reduced protective interaction between miR-128-3p and circRERE. Accordingly, overexpression of circRERE rescued exaggerated synapse formation upon circRERE knockdown in a miR-128-3p binding site-specific manner. Overall, our results uncover circRERE-mediated stabilization of miR-128-3p as a novel mechanism to restrict the formation of silent excitatory synaptic co-clusters and more generally implicate circRNA-dependent microRNA regulation in the control of synapse development and function.

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“…In order to identify differentially expressed circRNAs in HD, Marin et al, did microarray analysis of murine cell line model expressing mutant HTT. The authors reported that differentially expressed circRNAs were found to regulate MAPK pathway, Long-term depression pathway as well as dopaminergic synapse which have been previously involved in HD physiopathology ( Marfil-Marin et al, 2021 ). The authors concluded that in-depth understanding of the HD specific circRNA-miRNA-mRNA axis can lead to identify novel biomarkers and potential therapeutic targets for HD.…”

Section: The Enigmatic Connection Between Circrnas Autophagy and Neur...mentioning

confidence: 99%

Brain-protective mechanisms of autophagy associated circRNAs: Kick starting self-cleaning mode in brain cells via circRNAs as a potential therapeutic approach for neurodegenerative diseases

Basri

Awan²,

Yang³

et al. 2023

Front. Mol. Neurosci.

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Altered autophagy is a hallmark of neurodegeneration but how autophagy is regulated in the brain and dysfunctional autophagy leads to neuronal death has remained cryptic. Being a key cellular waste-recycling and housekeeping system, autophagy is implicated in a range of brain disorders and altering autophagy flux could be an effective therapeutic strategy and has the potential for clinical applications down the road. Tight regulation of proteins and organelles in order to meet the needs of complex neuronal physiology suggests that there is distinct regulatory pattern of neuronal autophagy as compared to non-neuronal cells and nervous system might have its own separate regulator of autophagy. Evidence has shown that circRNAs participates in the biological processes of autophagosome assembly. The regulatory networks between circRNAs, autophagy, and neurodegeneration remains unknown and warrants further investigation. Understanding the interplay between autophagy, circRNAs and neurodegeneration requires a knowledge of the multiple steps and regulatory interactions involved in the autophagy pathway which might provide a valuable resource for the diagnosis and therapy of neurodegenerative diseases. In this review, we aimed to summarize the latest studies on the role of brain-protective mechanisms of autophagy associated circRNAs in neurodegenerative diseases (including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Spinal Muscular Atrophy, Amyotrophic Lateral Sclerosis, and Friedreich’s ataxia) and how this knowledge can be leveraged for the development of novel therapeutics against them. Autophagy stimulation might be potential one-size-fits-all therapy for neurodegenerative disease as per considerable body of evidence, therefore future research on brain-protective mechanisms of autophagy associated circRNAs will illuminate an important feature of nervous system biology and will open the door to new approaches for treating neurodegenerative diseases.

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circRNA Regulates Dopaminergic Synapse, MAPK, and Long-term Depression Pathways in Huntington Disease

Cited by 8 publications

References 37 publications

Current Diagnostic Methods and Non-Coding RNAs as Possible Biomarkers in Huntington’s Disease

Current Diagnostic Methods and Non-Coding RNAs as Possible Biomarkers in Huntington’s Disease

A functional screen uncovers circular RNAs regulating excitatory synaptogenesis in hippocampal neurons

Brain-protective mechanisms of autophagy associated circRNAs: Kick starting self-cleaning mode in brain cells via circRNAs as a potential therapeutic approach for neurodegenerative diseases

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