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.

Machado–Joseph disease/spinocerebellar ataxia type 3: lessons from disease pathogenesis and clues into therapy

“…More recently, miRNA biogenesis was described to be impaired in MJD/SCA3, as several genes regulating that process are down‐regulated in different disease models (Carmona et al . ). The study also reported that three microRNAs (miR‐9, miR‐181a, and miR‐494) that interact with the 3′ untranslated region (3′UTR) of ataxin‐3 mRNA show a dysregulated expression in brain samples from MJD/SCA3 patients (Carmona et al .…”

Genetics, Mechanisms, and Therapeutic Progress in Polyglutamine Spinocerebellar Ataxias

“…In a SCA3 animal model and human neurons, 3 miRNAs were identified that interact with the ATXN3 3′ UTR and whose expression is dysregulated. Injecting lentiviral vectors encoding for these miRNAs in the striatum of 5-week-old SCA3 mice resulted in reduction of ataxin-3 levels and nuclear aggregates and improvement of neuronal dysfunction [ 193 ]. Similar results have been obtained with adeno-associated virus (AAV)-mediated delivery of miR-3191-5p in SCA6 mice.…”

Welcome to the 10th volume of Epigenomics

“…This phenomenon is further magnified because miR-9/9* transcription depends on REST. Aberrant expression of miR-9 has also been observed in the cerebella of mouse model of SCA3 [137] and SCA1 [140], being downregulated in SCA3 and upregulated in SCA1. The miR-9 dysregulation in SCA3 is proposed to be related with an impairment in miRNA biogenesis.…”

“…Interestingly, ataxin-2, the protein involved in SCA2 disease, might be required for miRNA function, as lack of ataxin-2 impairs the repressive activity of several miRNAs [136]. In SCA3, miR-181a and miR-494, which interact with the ATXN3-3 -UTR, are found dysregulated in human MJD neurons as well as other MJD cell and animal models, and overexpression of these miRNAs alleviated MJD neuropathology in vivo [137]. In SCA17, downregulation of miR-29a and miR-29b is observed in a cellular model of SCA17, which was inversely correlated with BACE1 expression [138].…”