title: Unravelling Endogenous MicroRNA System Dysfunction as a New Pathophysiological Mechanism in Machado-Joseph Disease.
abstract: Machado-Joseph disease (MJD) is a genetic neurodegenerative disease caused by an expanded polyglutamine tract within the protein ataxin-3 (ATXN3). Despite current efforts, MJD's mechanism of pathogenesis remains unclear and no disease-modifying treatment is available. Therefore, in this study, we investigated (1) the role of the 3' UTR of ATXN3, a putative microRNA (miRNA) target, (2) whether miRNA biogenesis and machinery are dysfunctional in MJD, and (3) which specific miRNAs target ATXN3-3' UTR and whether they can alleviate MJD neuropathology in vivo. Our results demonstrate that endogenous miRNAs, by targeting sequences in the 3' UTR, robustly reduce ATXN3 expression and aggregation in vitro and neurodegeneration and neuroinflammation in vivo. Importantly, we found an abnormal MJD-associated downregulation of genes involved in miRNA biogenesis and silencing activity. Finally, we identified three miRNAs-mir-9, mir-181a, and mir-494-that interact with the ATXN3-3' UTR and whose expression is dysregulated in human MJD neurons and in other MJD cell and animal models. Furthermore, overexpression of these miRNAs in mice resulted in reduction of mutATXN3 levels, aggregate counts, and neuronal dysfunction. Altogether, these findings indicate that endogenous miRNAs and the 3' UTR of ATXN3 play a crucial role in MJD pathogenesis and provide a promising opportunity for MJD treatment.
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, Coimbra 3004-504, Portugal; Faculty of Pharmacy, University of Coimbra, Coimbra 3000-548, Portugal.
authors.forename: Vitor
authors.initials: V
authors.lastname: Carmona
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, Coimbra 3004-504, Portugal; Faculty of Pharmacy, University of Coimbra, Coimbra 3000-548, Portugal.
authors.forename: Janete
authors.initials: J
authors.lastname: Cunha-Santos
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, Coimbra 3004-504, Portugal; Faculty of Pharmacy, University of Coimbra, Coimbra 3000-548, Portugal.
authors.forename: Isabel
authors.initials: I
authors.lastname: Onofre
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, Coimbra 3004-504, Portugal.
authors.forename: Ana Teresa
authors.initials: AT
authors.lastname: Simões
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, Coimbra 3004-504, Portugal.
authors.forename: Udaya
authors.initials: U
authors.lastname: Vijayakumar
authors.affiliation: The Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Beverly L
authors.initials: BL
authors.lastname: Davidson
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, Coimbra 3004-504, Portugal; Faculty of Pharmacy, University of Coimbra, Coimbra 3000-548, Portugal. Electronic address: luispa@cnc.uc.pt.
authors.forename: Luís
authors.initials: L
authors.lastname: Pereira de Almeida
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D000067699:Ataxin-3 / Q000235:genetics; D002460:Cell Line; D004195:Disease Models, Animal; D015870:Gene Expression; D005786:Gene Expression Regulation; D023061:Gene Order; D017930:Genes, Reporter; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D017827:Machado-Joseph Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics*; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D066263:Protein Aggregation, Pathological; D034622:RNA Interference; D020871:RNA Stability
chemical_list: D020413:3' Untranslated Regions; D035683:MicroRNAs; D000067699:Ataxin-3
keywords: 3′; Machado-Joseph disease; SCA3; UTR; gene therapy; lentivirus; mechanism of disease; microRNA; microRNA machinery dysregulation