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.
Highlights
The processing of mRNAs includes three essential modifications, capping, splicing and polyadenylation, which mainly occur at the sites of transcription[1,2]
Our results demonstrate the nuclear accumulation of poly(A) RNAs in poly(A) RNA granules (PARGs) enriched in the RNA-binding protein Sam[68], which is an alternative splicing regulator of pre-mRNAs35–37
We investigated whether the nuclear accumulation of polyadenylated mRNAs in PARGs was associated with the splicing dysfunction of four genes, choline acetyltransferase (Chat), Chodl, Myh[9] and Myh[14], which are important for motor neuron (MN) maturation and synapse development and function[28,57]
Summary
The processing of mRNAs includes three essential modifications, capping, splicing and polyadenylation, which mainly occur at the sites of transcription (co-transcriptional)[1,2]. Upon the completion of co-transcriptional processing, mRNAs are exported to the cytoplasm as parts of messenger ribonucleoprotein particles for translation and degradation During their nuclear journey, mRNAs associate with several RNA-binding proteins that contribute to the regulation of their processing and exportation. MRNAs associate with several RNA-binding proteins that contribute to the regulation of their processing and exportation On their nuclear route, some normal and incompletely spliced mRNAs are trafficked and may be retained in nuclear speckles[2,5,6,7]. The formation of PARGs associates with variations in the alternative splicing regulation of several mRNAs, including the Sam68-dependent Bcl-x and Nrxn-1 mRNAs. the massive accumulation of PARGs in MNs is accompanied by cytoplasmic depletion of polyadenylated mRNAs, supporting the existence of a severe dysfunction of both mRNA processing and translation, which may be an important pathogenic factor in SMA
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