Autophagy Inhibition Favors Survival of Rubrospinal Neurons After Spinal Cord Hemisection.

Maria Teresa Viscomi, Elisa Bisicchia, Laura Latini, Virve Cavallucci, Valeria Sasso, Vanessa Nicolin, Marco Molinari, Marcello D’Amelio

Risultato della ricerca: Contributo in rivistaArticolo in rivista

17 Citazioni (Scopus)

Abstract

Spinal cord injuries (SCIs) are devastating conditions of the central nervous system (CNS) for which there are no restorative therapies. Neuronal death at the primary lesion site and in remote regions that are functionally connected to it is one of the major contributors to neurological deficits following SCI.Disruption of autophagic flux induces neuronal death in many CNS injuries, but its mechanism and relationship with remote cell death after SCI are unknown. We examined the function and effects of the modulation of autophagy on the fate of axotomized rubrospinal neurons in a rat model of spinal cord dorsal hemisection (SCH) at the cervical level. Following SCH, we observed an accumulation of LC3-positive autophagosomes (APs) in the axotomized neurons 1 and 5 days after injury. Furthermore, this accumulation was not attributed to greater initiation of autophagy but was caused by a decrease in AP clearance, as demonstrated by the build-up of p62, a widely used marker of the induction of autophagy. In axotomized rubrospinal neurons, the disruption of autophagic flux correlated strongly with remote neuronal death and worse functional recovery. Inhibition of AP biogenesis by 3-methyladenine (3-MA) significantly attenuated remote degeneration and improved spontaneous functional recovery, consistent with the detrimental effects of autophagy in remote damage after SCH. Collectively, our results demonstrate that autophagic flux is blocked in axotomized neurons on SCI and that the inhibition of AP formation improves their survival. Thus, autophagy is a promising target for the development of therapeutic interventions in the treatment of SCIs.
Lingua originaleEnglish
pagine (da-a)4896-4907
Numero di pagine12
RivistaMolecular Neurobiology
Stato di pubblicazionePubblicato - 2017

Keywords

  • autophagy

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