Abstract: Spinal muscular atrophy (SMA) is caused by a homozygous deletion or mutation in the survival motor neuron 1
(SMN1) gene that leads to reduced levels of SMN protein resulting in degeneration of motor neurons (MNs). The
best known functions of SMN is the biogenesis of spliceosomal snRNPs. Linked to this function, Cajal bodies (CBs)
are involved in the assembly of spliceosomal (snRNPs) and nucleolar (snoRNPs) ribonucleoproteins required for
pre-mRNA and pre-rRNA processing. Recent studies support that the interaction between CBs and nucleoli,
which are especially prominent in neurons, is essential for the nucleolar rRNA homeostasis.
We use the SMN?7 murine model of type I SMA to investigate the cellular basis of the dysfunction of RNA metabolism
in MNs. SMN deficiency in postnatal MNs produces a depletion of functional CBs and relocalization of
coilin, which is a scaffold protein of CBs, in snRNP-free perinucleolar caps or within the nucleolus. Disruption
of CBs is the earliest nuclear sign of MN degeneration.We demonstrate that depletion of CBs,with loss of CB-nucleolus
interactions, induces a progressive nucleolar dysfunction in ribosome biogenesis. It includes reorganization
and loss of nucleolar transcription units, segregation of dense fibrillar and granular components, retention of
SUMO-conjugated proteins in intranucleolar bodies and a reactive, compensatory, up-regulation of mature 18S
rRNA and genes encoding key nucleolar proteins, such as upstream binding factor, fibrillarin, nucleolin and
nucleophosmin.
We propose that CB depletion and nucleolar alterations are essential components of the dysfunction of RNA metabolism
in SMA.
Otras publicaciones de la misma revista o congreso con autores/as de la Universidad de Cantabria