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.