Unravelling Endogenous MicroRNA System Dysfunction as a New Pathophysiological Mechanism in Machado-Joseph Disease

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 in...

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Published in:Molecular therapy 2017-04, Vol.25 (4), p.1038-1055
Main Authors: Carmona, Vitor, Cunha-Santos, Janete, Onofre, Isabel, Simões, Ana Teresa, Vijayakumar, Udaya, Davidson, Beverly L., Pereira de Almeida, Luís
Format: Article
Language:English
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Animal models
Animals
Ataxia
Ataxin
Ataxin-3 - genetics
Brain research
Cell culture
Cell Line
Disease
Disease Models, Animal
Experiments
Gene Expression
Gene Expression Regulation
Gene Order
gene therapy
Genes, Reporter
Genetic Vectors - genetics
Humans
Inflammation
Insects
lentivirus
Lentivirus - genetics
Machado-Joseph disease
Machado-Joseph Disease - genetics
Machado-Joseph Disease - metabolism
Machado-Joseph Disease - pathology
mechanism of disease
Mice
Mice, Transgenic
microRNA
microRNA machinery dysregulation
MicroRNAs - genetics
miRNA
Mutation
Neurodegeneration
Neurodegenerative diseases
Neurons - metabolism
Neuropathology
Original
Pathogenesis
Penicillin
Polyglutamine
Protein Aggregation, Pathological
Proteins
Quality control
RNA Interference
RNA Stability
Rodents
SCA3
Studies
Trinucleotide repeat diseases
UTR
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Summary: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. [Display omitted] Machado-Joseph disease (MJD) is a fatal neurodegenerative disorder caused by a polyglutamine expansion in the ataxin-3 protein. In this study, Carmona and colleagues identified multiple microRNAs regulating ataxin-3 expression, which are also dysregulated in MJD. Brain delivery of these microRNAs may represent a promising therapeutic approach for MJD.
ISSN:1525-0016
1525-0024
DOI:10.1016/j.ymthe.2017.01.021