circRNA Regulates Dopaminergic Synapse, MAPK, and Long-term Depression Pathways in Huntington Disease Ernesto Marfil-Marin 1 & Mónica Santamaría-Olmedo 1 & Adriana PerezGrovas-Saltijeral 1 & Margarita Valdes-Flores 1 & Adriana Ochoa-Morales 2 & Aurelio Jara-Prado 2 & Rosalba Sevilla-Montoya 3 & Alejandra Camacho-Molina 2,4 & Alberto Hidalgo-Bravo 1 Received: 30 June 2021 /Accepted: 17 August 2021 # The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021 Abstract Huntington disease (HD) is the most common neurogenetic disorder caused by expansion of the CAG repeat in the HTT gene; nevertheless, the molecular bases of the disease are not fully understood. Non-coding RNAs have demonstrated to be involved in the physiopathology of HD. However, the role of circRNAs has not been investigated. The aim of this study was to identify the circRNAs with differential expression in a murine cell line model of HD and to identify the biological pathways regulated by the differentially expressed circRNAs. CircRNA expression was analyzed through a microarray, which specifically detects circular species of RNA. The expression patterns between a murine cell line expressing mutant Huntingtin and cells expressing wild-type Huntingtin were compared. We predicted the miRNAs with binding sites for the differentially expressed circRNAs and the corresponding target genes for those miRNAs. Using the target genes, we performed a function enrichment analysis. We identified 23 circRNAs differentially expressed, 19 downregulated and four upregulated. Most of the downregulated circRNAs derive from the Rere gene. The dopaminergic synapse, MAPK, and long-term depression pathways were significantly enriched. The three identified pathways have been previously associated with the physiopathology of HD. The understanding of the circRNA-miRNA-mRNA network involved in the molecular mechanisms driving HD can lead us to identify novel bio- markers and potential therapeutic targets. To the best of our knowledge, this is the first study analyzing circRNAs in a model of Huntington disease. Keywords Huntington disease . circRNA . Dopaminergic synapse pathway . MAPK pathway . Mutant huntingtin Introduction Huntington’s disease (HD) is one of the most common hered- itary neurodegenerative disorders, reported prevalence per 100,000 habitants varies largely across populations, from 0.04 in Asia to 7.33 in North America [1]. Clinical manifes- tations of HD include motor, cognitive, and psychiatric signs and symptoms. The motor manifestations are the most evi- dent, with chorea being the most characteristic. However, the cognitive and psychiatric manifestations, acquire great im- portance, since they involve important aspects of morbidity- mortality [2, 3]. HD is caused by mutation in the HTT gene, which encodes for the protein huntingtin. The molecular defect is an expan- sion of the CAG repeat, which encodes for glutamine (Q), in exon 1 of HTT [4]. Alleles possessing 26 or less repeats are considered normal, from 27–35 repeats, there is a risk of trans- mitting the disease secondary to expansion through parental meiosis, from 36–39 repeats, incomplete penetrance has been * Alejandra Camacho-Molina dralejandragenetica@gmail.com * Alberto Hidalgo-Bravo dr_genetica@yahoo.com 1 Department of Genetics, National Institute of Rehabilitation, Calzada Mexico-Xochimilco 289. Arenal de Guadalupe. Z. C, 14389 Mexico City, Mexico 2 Department of Neurogenetics, National Institute of Neurology and Neurosurgery, Av. Insurgentes Sur 3877, La Fama, Z.C, 14269 Mexico City, Mexico 3 Department of Genetics and Human Genomics, National Institute of Perinatology, Montes Urales 800, Lomas-Virreyes, Lomas de Chapultepec IV Secc. Z. C, 11000 Mexico City, Mexico 4 Present address: Rare Disease Coordination, Institute for Social Security and Services for State Workers, Av. San Fernando 547, Toriello Guerra, Z.C, 14050 Mexico City, Mexico https://doi.org/10.1007/s12035-021-02536-1 / Published online: 2 September 2021 Molecular Neurobiology (2021) 58:6222–6231 1 3