Autophagy Inhibition Favors Survival of Rubrospinal Neurons After Spinal Cord Hemisection

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

Research output: Contribution to journalArticle

7 Citations (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.

Original languageEnglish
Pages (from-to)1-12
Number of pages12
JournalMolecular Neurobiology
DOIs
Publication statusAccepted/In press - Aug 11 2016

Fingerprint

Autophagy
Spinal Cord Injuries
Spinal Cord
Neurons
Central Nervous System
Nervous System Trauma
Cell Death
Autophagosomes
Wounds and Injuries
Therapeutics

Keywords

  • Autophagosomes
  • Autophagy
  • Autophagy flux
  • Neurodegeneration
  • Remote damage
  • Spinal cord injury

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

Cite this

Bisicchia, E., Latini, L., Cavallucci, V., Sasso, V., Nicolin, V., Molinari, M., ... Viscomi, M. T. (Accepted/In press). Autophagy Inhibition Favors Survival of Rubrospinal Neurons After Spinal Cord Hemisection. Molecular Neurobiology, 1-12. https://doi.org/10.1007/s12035-016-0031-z

Autophagy Inhibition Favors Survival of Rubrospinal Neurons After Spinal Cord Hemisection. / Bisicchia, Elisa; Latini, Laura; Cavallucci, Virve; Sasso, Valeria; Nicolin, Vanessa; Molinari, Marco; D’Amelio, Marcello; Viscomi, Maria Teresa.

In: Molecular Neurobiology, 11.08.2016, p. 1-12.

Research output: Contribution to journalArticle

Bisicchia, Elisa ; Latini, Laura ; Cavallucci, Virve ; Sasso, Valeria ; Nicolin, Vanessa ; Molinari, Marco ; D’Amelio, Marcello ; Viscomi, Maria Teresa. / Autophagy Inhibition Favors Survival of Rubrospinal Neurons After Spinal Cord Hemisection. In: Molecular Neurobiology. 2016 ; pp. 1-12.
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