1. Stimulation of autophagy by rapamycin protects neurons from remote degeneration after acute focal brain damage.
- Author
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Viscomi MT, D'Amelio M, Cavallucci V, Latini L, Bisicchia E, Nazio F, Fanelli F, Maccarrone M, Moreno S, Cecconi F, and Molinari M
- Subjects
- Animals, Apoptosis Regulatory Proteins metabolism, Axotomy, Beclin-1, Brain Injuries drug therapy, Brain Injuries pathology, Cerebellum drug effects, Cerebellum surgery, Chloroquine pharmacology, Cytochromes c metabolism, Mice, Mice, Inbred C57BL, Mitochondria drug effects, Mitochondria pathology, Mitochondria ultrastructure, Nerve Degeneration drug therapy, Nerve Degeneration etiology, Nerve Degeneration pathology, Neurons cytology, Neurons pathology, Neurons ultrastructure, Neuroprotective Agents therapeutic use, Phagosomes drug effects, Phagosomes metabolism, Phagosomes ultrastructure, Sirolimus therapeutic use, Autophagy drug effects, Brain Injuries complications, Cytoprotection drug effects, Nerve Degeneration prevention & control, Neurons drug effects, Neuroprotective Agents pharmacology, Sirolimus pharmacology
- 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.
- Published
- 2012
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