Article ; Online: Upregulation of β-catenin due to loss of miR-139 contributes to motor neuron death in amyotrophic lateral sclerosis.
2022 Volume 17, Issue 7, Page(s) 1650–1665
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of motor neurons (MNs). There are no effective treatments and patients usually die within 2-5 years of diagnosis. Emerging commonalities between familial ... ...
| Abstract | Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of motor neurons (MNs). There are no effective treatments and patients usually die within 2-5 years of diagnosis. Emerging commonalities between familial and sporadic cases of this complex multifactorial disorder include disruption to RNA processing and cytoplasmic inclusion bodies containing TDP-43 and/or FUS protein aggregates. Both TDP-43 and FUS have been implicated in RNA processing functions, including microRNA biogenesis, transcription, and splicing. In this study, we explore the misexpression of microRNAs in an iPSC-based disease model of FUS ALS. We identify the downregulation of miR-139, an MN-enriched microRNA, in FUS and sporadic ALS MN. We discover that miR-139 downregulation leads to the activation of canonical WNT signaling and demonstrate that the WNT transcriptional mediator β-catenin is a major driver of MN degeneration in ALS. Our results highlight the importance of homeostatic RNA networks in ALS. |
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| MeSH term(s) | Amyotrophic Lateral Sclerosis/genetics ; Amyotrophic Lateral Sclerosis/metabolism ; DNA-Binding Proteins/metabolism ; Humans ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Motor Neurons/metabolism ; Mutation ; Neurodegenerative Diseases/metabolism ; RNA-Binding Protein FUS/genetics ; RNA-Binding Protein FUS/metabolism ; Up-Regulation/genetics ; beta Catenin/genetics ; beta Catenin/metabolism |
| Chemical Substances | DNA-Binding Proteins ; MIRN139 microRNA, human ; MicroRNAs ; RNA-Binding Protein FUS ; beta Catenin |
| Language | English |
| Publishing date | 2022-06-23 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 2720528-9 |
| ISSN | 2213-6711 ; 2213-6711 |
| ISSN (online) | 2213-6711 |
| ISSN | 2213-6711 |
| DOI | 10.1016/j.stemcr.2022.05.019 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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