title: Stimulation of autophagy by rapamycin protects neurons from remote degeneration after acute focal brain damage.
abstract: Autophagy is the evolutionarily conserved degradation and recycling of cellular constituents. In mammals, autophagy is implicated in the pathogenesis of many neurodegenerative diseases. However, its involvement in acute brain damage is unknown. This study addresses the function of autophagy in neurodegeneration that has been induced by acute focal cerebellar lesions. We provide morphological, ultrastructural, and biochemical evidence that lesions in a cerebellar hemisphere activate autophagy in axotomized precerebellar neurons. Through time course analyses of the apoptotic cascade, we determined mitochondrial dysfunction to be the early trigger of degeneration. Further, the stimulation of autophagy by rapamycin and the employment of mice with impaired autophagic responses allowed us to demonstrate that autophagy protects from damage promoting functional recovery. These findings have therapeutic significance, demonstrating the potential of pro-autophagy treatments for acute brain pathologies, such as stroke and brain trauma.
authors.affiliation: IRCCS S. Lucia Foundation, Rome, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Viscomi
authors.forename: Marcello
authors.initials: M
authors.lastname: D'Amelio
authors.forename: Virve
authors.initials: V
authors.lastname: Cavallucci
authors.forename: Laura
authors.initials: L
authors.lastname: Latini
authors.forename: Elisa
authors.initials: E
authors.lastname: Bisicchia
authors.forename: Francesca
authors.initials: F
authors.lastname: Nazio
authors.forename: Francesca
authors.initials: F
authors.lastname: Fanelli
authors.forename: Mauro
authors.initials: M
authors.lastname: Maccarrone
authors.forename: Sandra
authors.initials: S
authors.lastname: Moreno
authors.forename: Francesco
authors.initials: F
authors.lastname: Cecconi
authors.forename: Marco
authors.initials: M
authors.lastname: Molinari
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D019771:Axotomy; D000071186:Beclin-1; D001930:Brain Injuries / Q000150:complications* / Q000188:drug therapy / Q000473:pathology; D002531:Cerebellum / Q000187:drug effects / Q000601:surgery; D002738:Chloroquine / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D009410:Nerve Degeneration / Q000188:drug therapy / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D010588:Phagosomes / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D020123:Sirolimus / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D018696:Neuroprotective Agents; D002738:Chloroquine; D045304:Cytochromes c; D020123:Sirolimus