Axonal Degeneration Is Mediated by the Mitochondrial Permeability Transition Pore
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2011-01-19Metadata
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Barrientos, Sebastián A.
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Axonal Degeneration Is Mediated by the Mitochondrial Permeability Transition Pore
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Abstract
Axonal degeneration is an active process that has been associated with neurodegenerative conditions triggered by mechanical, metabolic, infectious, toxic, hereditary and inflammatory stimuli. This degenerative process can cause permanent loss of function, so it represents a focus for neuroprotective strategies. Several signaling pathways are implicated in axonal degeneration, but identification of an integrative mechanism for this self-destructive process has remained elusive. Here, we show that rapid axonal degeneration triggered by distinct mechanical and toxic insults is dependent on the activation of the mitochondrial permeability transition pore (mPTP). Both pharmacological and genetic targeting of cyclophilin D, a functional component of the mPTP, protects severed axons and vincristine-treated neurons from axonal degeneration in ex vivo and in vitro mouse and rat model systems. These effects were observed in axons from both the peripheral and central nervous system. Our results suggest that the mPTPis a key effector of axonal degeneration, upon which several independent signaling pathways converge. Since axonal and synapse degeneration are increasingly considered early pathological events in neurodegeneration, our work identifies a potential target for therapeutic intervention in a wide variety of conditions that lead to loss of axons and subsequent functional impairment.
Patrocinador
Fondo Nacional de Desarrollo Cientifico y Tecnologico (FONDECYT) 1070377
1070444
Millennium Nucleus P-07-011-F
P-07-048-F
National Institutes of Health R01-NS049041
R01-NS041596
Fondo de Financiamiento de Centros de Excelencia en Investigacion (FONDAP) 15010006
Muscular Dystrophy Association
CHDI Foundation Inc.
M. J. Fox Foundation for Parkinson Research
International Centre for Genetic Engineering and Biotechnology
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URI: https://repositorio.uchile.cl/handle/2250/128866
DOI: DOI: 10.1523/JNEUROSCI.4065-10.2011
ISSN: 0270-6474
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JOURNAL OF NEUROSCIENCE Volume: 31 Issue: 3 Pages: 966-978 Published: JAN 19 2011
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