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Spinal muscular atrophy (SMA) is a genetic disorder characterized by degeneration of spinal cord motoneurons (MNs), resulting in muscular atrophy and weakness. SMA is caused by mutations in the Survival Motor Neuron 1 (SMN1) gene and decreased SMN protein. SMN is ubiquitously expressed and has a general role in the assembly of small nuclear ribonucleoproteins and pre-mRNA splicing requirements. SMN reduction causes neurite degeneration and cell death without classical apoptotic features, but the direct events leading to SMN degeneration in SMA are still unknown. Autophagy is a conserved lysosomal protein degradation pathway whose precise roles in neurodegenerative diseases remain largely unknown. In particular, it is unclear whether autophagosome accumulation is protective or destructive, but the accumulation of autophagosomes in the neuritic beadings observed in several neurite degeneration models suggests a close relationship between the autophagic process and neurite collapse. In the present work, we describe an increase in the levels of the autophagy markers including autophagosomes, Beclin1 and light chain (LC)3-II proteins in cultured mouse spinal cord MNs from two SMA cellular models, suggesting an upregulation of the autophagy process in Smn (murine survival motor neuron protein)-reduced MNs. Overexpression of Bcl-xL counteracts LC3-II increase, contributing to the hypothesis that the protective role of Bcl-xL observed in some SMA models may be mediated by its role in autophagy inhibition. Our in vitro experimental data indicate an upregulation in the autophagy process and autophagosome accumulation in the pathogenesis of SMA, thus providing a valuable clue in understanding the mechanisms of axonal degeneration and a possible therapeutic target in the treatment of SMA.This work was supported by grants from GENAME(Defining targets for Therapeutics in SMA) to RMS; from Instituto de Salud CarlosIII, Fondo de Investigaciones Sanitarias (PI11-01047), Generalitat de Catalunya(SGR740) and Consolider-Ingenio 2010 (CSD2007-00020) to RMS. AG holds apost-doctoral contract from Genoma Espan˜a; SA holds a fellowship from Universitatde Lleida and AP holds a fellowship from Comissionat de Universitats i Recerca,Departament d’Innovacio´, Universitats i Empresa de la Generalitat de Catalunyaand Fons Social Europeu

Survival motor neuron protein reduction deregulates autophagy in spinal cord motoneurons in vitro