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Reorganization of Cajal bodies and nucleolar targeting of coilin in motor neurons of type I spinal muscular atrophy

Abstract: Type I spinal muscular atrophy (SMA) is an autosomal recessive disorder caused by loss or mutations of the survival motor neuron 1 (SMN1) gene. The reduction in SMN protein levels in SMA leads to degeneration and death of motor neurons. In this study, we have analyzed the nuclear reorganization of Cajal bodies, PML bodies and nucleoli in type I SMA motor neurons with homozygous deletion of exons 7 and 8 of the SMN1 gene. Western blot analysis is is revealed a marked reduction of SMN levels compared to the control sample. Using a neuronal dissociation procedure to perform a careful immunocytochemical and quantitative analysis of nuclear bodies, we demonstrated a severe decrease in the mean number of Cajal bodies per neuron and in the proportion of motor neurons containing these structures in type I SMA. Moreover, most Cajal bodies fail to recruit SMN and spliceosomal snRNPs, but contain the proteasome activator PA28, a molecular marker associated with the cellular stress response. Neuronal stress in SMA motor neurons also increases PML body number. The existence of chromatolysis and eccentric nuclei in SMA motor neurons correlates with Cajal body disruption and nucleolar relocalization of coil in, a Cajal body marker. Our results indicate that the Cajal body is a pathophysiological target in type I SMA motor neurons. They also suggest the Cajal body-dependent dysfunction of snRNP biogenesis and, therefore, pre-mRNA splicing in these neurons seems to be an essential component for SMA pathogenesis.

 Fuente: Histochemistry and Cell Biology, 2012, 137, 657-667

 Editorial: Springer

 Año de publicación: 2012

 Nº de páginas: 11

 Tipo de publicación: Artículo de Revista

 DOI: 10.1007/s00418-012-0921-8

 ISSN: 0948-6143,1432-119X

 Proyecto español: BFU2008-00175; BFU2011-23983

 Url de la publicación: https://doi.org/10.1007/s00418-012-0921-8

Autoría

OLGA TAPIA MARTINEZ

ROCIO BENGOECHEA IBACETA

ROSA MARIA ARTEAGA MANJON-CABEZA

JOSE FERNANDO VAL BERNAL

TIZZANO, EDUARDO F.

MARIA TERESA BERCIANO BLANCO