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Accumulation of poly(A) RNA in nuclear granules enriched in Sam68 in motor neurons from the SMNA7 mouse model of SMA

Abstract: Spinal muscular atrophy (SMA) is a severe motor neuron (MN) disease caused by the deletion or mutation of the survival motor neuron 1 (SMN1) gene, which results in reduced levels of the SMN protein and the selective degeneration of lower MNs. The best-known function of SMN is the biogenesis of spliceosomal snRNPs, the major components of the pre-mRNA splicing machinery. Therefore, SMN deficiency in SMA leads to widespread splicing abnormalities. We used the SMN?7 mouse model of SMA to investigate the cellular reorganization of polyadenylated mRNAs associated with the splicing dysfunction in MNs. We demonstrate that SMN deficiency induced the abnormal nuclear accumulation in euchromatin domains of poly(A) RNA granules (PARGs) enriched in the splicing regulator Sam68. However, these granules lacked other RNA-binding proteins, such as TDP43, PABPN1, hnRNPA12B, REF and Y14, which are essential for mRNA processing and nuclear export. These effects were accompanied by changes in the alternative splicing of the Sam68-dependent Bcl-x and Nrnx1 genes, as well as changes in the relative accumulation of the intron-containing Chat, Chodl, Myh9 and Myh14 mRNAs, which are all important for MN functions. PARG-containing MNs were observed at presymptomatic SMA stage, increasing their number during the symptomatic stage. Moreover, the massive accumulations of poly(A) RNA granules in MNs was accompanied by the cytoplasmic depletion of polyadenylated mRNAs for their translation. We suggest that the SMN-dependent abnormal accumulation of polyadenylated mRNAs and Sam68 in PARGs reflects a severe dysfunction of both mRNA processing and translation, which could contribute to SMA pathogenesis.

Otras publicaciones de la misma revista o congreso con autores/as de la Universidad de Cantabria

 Fuente: Sci Rep. 2018 Jun 25;8(1):9646

Editorial: Nature Publishing Group

 Año de publicación: 2018

Nº de páginas: 16

Tipo de publicación: Artículo de Revista

 DOI: 10.1038/s41598-018-27821-3

ISSN: 2045-2322

Proyecto español: BFU2014-54754-P ; SAF2015-70801-R

Url de la publicación: https://dx.doi.org/10.1038/s41598-018-27821-3

Autores/as

JOSEP ORIOL NARCIS MAJOS

OLGA TAPIA MARTINEZ

TARABAL, OLGA

PIEDRAFITA, LÍDIA

CALDERÓ, JORDI

MARIA TERESA BERCIANO BLANCO

MIGUEL ANGEL LAFARGA COSCOJUELA