Upregulation of ß-catenin due to loss of miR-139 contributes to motor neuron death in amyotrophic lateral sclerosis.
Stem Cell Reports
; 17(7): 1650-1665, 2022 07 12.
Article
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| MEDLINE
| ID: mdl-35750046
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 ß-catenin is a major driver of MN degeneration in ALS. Our results highlight the importance of homeostatic RNA networks in ALS.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Enfermedades Neurodegenerativas
/
MicroARNs
/
Esclerosis Amiotrófica Lateral
Límite:
Humans
Idioma:
En
Revista:
Stem Cell Reports
Año:
2022
Tipo del documento:
Article
País de afiliación:
Reino Unido