Upregulation of miR-25 and miR-181 Family Members Correlates with Reduced Expression of ATXN3 in Lymphocytes from SCA3 Patients
| Autor: | Bernd O. Evert, Sybille Krauss, Stephanie Weber, Katlynn Carter, Rohit Nalavade |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
congenital hereditary and neonatal diseases and abnormalities Cell Biology MIRN25 microRNA human 03 medical and health sciences genetics [Ataxin-3] 0302 clinical medicine Downregulation and upregulation metabolism [MicroRNAs] ddc:570 genetics [Machado-Joseph Disease] Gene expression microRNA medicine Gene silencing Cytotoxic T cell Humans Orthopedics and Sports Medicine genetics [MicroRNAs] Lymphocytes Ataxin-3 3' Untranslated Regions metabolism [Repressor Proteins] metabolism [Ataxin-3] ATXN3 protein human General Medicine Machado-Joseph Disease medicine.disease Cell biology Reverse transcription polymerase chain reaction Repressor Proteins genetics [Repressor Proteins] MicroRNAs 030104 developmental biology medicine.anatomical_structure metabolism [Lymphocytes] Emergency Medicine Spinocerebellar ataxia metabolism [Machado-Joseph Disease] 030217 neurology & neurosurgery MIrn181 microRNA human HeLa Cells |
| Zdroj: | MicroRNA 8(1), 76-85 (2018). doi:10.2174/2211536607666180821162403 |
| ISSN: | 2211-5374 |
| DOI: | 10.2174/2211536607666180821162403 |
| Popis: | Background: Spinocerebellar ataxia type 3 (SCA3), the most common spinocerebellar ataxia, is caused by a polyglutamine (polyQ) expansion in the protein ataxin-3 (ATXN3). Silencing the expression of polyQ-expanded ATXN3 rescues the cellular disease phenotype. Objective: This study investigated the differential expression of microRNAs (miRNAs), small noncoding RNAs targeting gene expression, in lymphoblastoid cells (LCs) from SCA3 patients and the capability of identified deregulated miRNAs to target and alter ATXN3 expression. Methods: MiRNA profiling was performed by microarray hybridization of total RNA from control and SCA3-LCs. The capability of the identified miRNAs and their target sites to suppress ATXN3 expression was analyzed using mutagenesis, reverse transcription PCR, immunoblotting, luciferase reporter assays, mimics and precursors of the identified miRNAs. Results: SCA3-LCs showed significantly decreased expression levels of ATXN3 and a significant upregulation of the ATXN3-3’UTR targeting miRNAs, miR-32 and miR-181c and closely related members of the miR-25 and miR-181 family, respectively. MiR-32 and miR-181c effectively targeted the 3’UTR of ATXN3 and suppressed the expression of ATXN3. Conclusions: The simultaneous upregulation of closely related miRNAs targeting the 3’UTR of ATXN3 and the significantly reduced ATXN3 expression levels in SCA3-LCs suggests that miR-25 and miR-181 family members cooperatively bind to the 3’UTR to suppress the expression of ATXN3. The findings further suggest that the upregulation of miR-25 and miR-181 family members in SCA3- LCs reflects a cell type-specific, protective mechanism to diminish polyQ-mediated cytotoxic effects. Thus, miRNA mimics of miR-25 and miR-181 family members may prove useful for the treatment of SCA3. |
| Databáze: | OpenAIRE |
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