Inhibition of autophagy delays motoneuron degeneration and extends lifespan in a mouse model of spinal muscular atrophy.

Détails

Ressource 1Télécharger: s41419-017-0086-4.pdf (2422.02 [Ko])
Etat: Serval
Version: Final published version
ID Serval
serval:BIB_42D723532C50
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Inhibition of autophagy delays motoneuron degeneration and extends lifespan in a mouse model of spinal muscular atrophy.
Périodique
Cell Death & Disease
Auteur(s)
Piras A., Schiaffino L., Boido M., Valsecchi V., Guglielmotto M., De Amicis E., Puyal J., Garcera A., Tamagno E., Soler R.M., Vercelli A.
ISSN
2041-4889 (Electronic)
Statut éditorial
Publié
Date de publication
2017
Peer-reviewed
Oui
Volume
8
Numéro
12
Pages
3223
Langue
anglais
Résumé
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.
Mots-clé
Adenine/analogs & derivatives, Adenine/therapeutic use, Animals, Apoptosis/drug effects, Autophagy/drug effects, Disease Models, Animal, Genotype, In Situ Nick-End Labeling, Mice, Motor Neurons/enzymology, Motor Neurons/metabolism, Muscular Atrophy, Spinal/drug therapy, Muscular Atrophy, Spinal/metabolism, Sirolimus/pharmacology
Pubmed
Web of science
Open Access
Oui
Création de la notice
10/01/2018 9:46
Dernière modification de la notice
08/05/2019 17:45
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