Inhibition of autophagy delays motoneuron degeneration and extends lifespan in a mouse model of spinal muscular atrophy
Amicis, Elena De
MetadataShow full item record
Spinal muscular atrophy (SMA) is a recessive autosomal neuromuscular disease, due to homozygous mutations or deletions in the telomeric survival motoneuron gene 1 (SMN1). SMA is characterized by motor impairment, muscle atrophy, and premature death following motor neuron (MN) degeneration. Emerging
evidence suggests that dysregulation of autophagy contributes to MN degeneration. We here investigated the role of autophagy in the SMNdelta7 mouse model of SMA II (intermediate form of the disease) which leads to motor impairment by postnatal day 5 (P5) and to death by P13. We first showed by immunoblots that Beclin 1 and LC3-II expression levels increased in the lumbar spinal cord of the SMA pups. Electron microscopy and immunofluorescence studies confirmed that autophagic markers were enhanced in the ventral horn of SMA pups. To clarify the role of autophagy, we administered intracerebroventricularly (at P3) either an autophagy inhibitor (3-methyladenine, 3-MA), or an autophagy inducer (rapamycin) in SMA pups. Motor behavior was assessed daily with different tests: tail suspension, righting reflex, and hindlimb suspension tests. 3-MA significantly improved motor performance, extended the lifespan, and delayed MN death in lumbar spinal cord (10372.36 ± 2716 MNs) compared to control-group (5148.38 ± 94 MNs). Inhibition of autophagy by 3-MA suppressed autophagosome formation, reduced the apoptotic activation (cleaved caspase-3 and Bcl2) and the appearance of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive neurons, underlining that apoptosis and autophagy pathways are intricately intertwined. Therefore, autophagy is likely involved in MN death in SMA II, suggesting that it might represent a promising target for delaying the progression of SMA in humans as well.
Is part ofCell Death and Disease, 2017, vol. 8, núm. 3223, p. 1-16
European research projects
The following license files are associated with this item:
Showing items related by title, author, creator and subject.
Calpain Inhibition Increases SMN Protein in Spinal Cord Motoneurons and Ameliorates the Spinal Muscular Atrophy Phenotype in Mice Fuente Ruiz, Sandra de la; Sansa Zaragoza, Alba; Periyakaruppiah, Ambika; Garcera, Ana; Soler i Tatché, Rosa Ma. (Springer Verlag, 2018)Spinal muscular atrophy (SMA), a leading genetic cause of infant death, is caused by the loss of survival motor neuron 1 (SMN1) gene. SMA is characterized by the degeneration and loss of spinal cord motoneurons (MNs), ...
Periyakaruppiah, Ambika; Fuente Ruiz, Sandra de la; Arumugam, Saravanan; Bahi i Pla, Núria; Garcera, Ana; Soler i Tatché, Rosa Ma. (Elsevier, 2016)SpinalMuscular Atrophy (SMA), a neurodegenerative disorder primarily affecting motoneurons (MNs), is caused by the loss of the Survival Motor Neuron 1 (SMN1) gene and reduced levels of full-length survival motor neuron (SMN) ...
Regulation of survival motor neuron protein by the nuclear factor-kappa B pathway in mouse spinal cord motoneurons Arumugam, Saravanan; Tasheva, Stefka Mincheva; Periyakaruppiah, Ambika; Fuente Ruiz, Sandra de la; Soler i Tatché, Rosa Ma.; Garcera, Ana (Springer Verlag, 2017-08-14)Survival motor neuron (SMN) protein deficiency causes the genetic neuromuscular disorder spinal muscular atrophy (SMA), characterized by spinal cord motoneuron degeneration. Since SMN protein level is critical to disease ...