Traumatic brain injury-induced axonal phenotypes react differently to treatment

详细信息    查看全文

• 作者：Anders H?nell ; John E. Greer ; Melissa J. McGinn…
• 关键词：Traumatic brain injury ; Axonal injury ; Mitochondrial permeability transition pore ; Cyclophilin D ; Wallerian degeneration ; Mouse
• 刊名：Acta Neuropathologica
• 出版年：2015
• 出版时间：February 2015
• 年：2015
• 卷：129
• 期：2
• 页码：317-332
• 全文大小：3,175 KB
• 参考文献：1. Alavian KN, Beutner G, Lazrove E, Sacchetti S, Park HA, Licznerski P et al (2014) An uncoupling channel within the c-subunit ring of the F1FO ATP synthase is the mitochondrial permeability transition pore. Proc Natl Acad Sci 111:10580-0585 CrossRef
  2. Avery MA, Rooney TM, Pandya JD, Wishart TM, Gillingwater TH, Geddes JW et al (2012) WldS prevents axon degeneration through increased mitochondrial flux and enhanced mitochondrial Ca2+ buffering. Curr Biol 22:596-00 CrossRef
  3. Baines CP, Kaiser RA, Purcell NH, Blair NS, Osinska H, Hambleton MA et al (2005) Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 434:658-62 CrossRef
  4. Barrientos SA, Martinez NW, Yoo S, Jara JS, Zamorano S, Hetz C et al (2011) Axonal degeneration is mediated by the mitochondrial permeability transition pore. J Neurosci 31:966-78 CrossRef
  5. Basso E, Fante L, Fowlkes J, Petronilli V, Forte MA, Bernardi P (2005) Properties of the permeability transition pore in mitochondria devoid of Cyclophilin D. J Biol Chem 280:18558-8561 CrossRef
  6. Beirowski B, Nogradi A, Babetto E, Garcia-Alias G, Coleman MP (2010) Mechanisms of axonal spheroid formation in central nervous system Wallerian degeneration. J Neuropathol Exp Neurol 69:455-72 CrossRef
  7. Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate—a practical and powerful approach to multiple testing. J Roy Stat Soc Ser B Methodol 57:289-00
  8. Bernardi P (2013) The mitochondrial permeability transition pore: a mystery solved? Front Physiol 4:95 CrossRef
  9. Bonora M, Bononi A, De Marchi E, Giorgi C, Lebiedzinska M, Marchi S et al (2013) Role of the c subunit of the FO ATP synthase in mitochondrial permeability transition. Cell Cycle 12:674-83 CrossRef
  10. Buki A, Okonkwo DO, Povlishock JT (1999) Postinjury cyclosporin A administration limits axonal damage and disconnection in traumatic brain injury. J Neurotrauma 16:511-21 CrossRef
  11. Buki A, Povlishock JT (2006) All roads lead to disconnection? Traumatic axonal injury revisited. Acta Neurochir (Wien) 148:181-93 (discussion 193-84) CrossRef
  12. Cesarovic N, Nicholls F, Rettich A, Kronen P, Hassig M, Jirkof P et al (2010) Isoflurane and sevoflurane provide equally effective anaesthesia in laboratory mice. Lab Anim 44:329-36 CrossRef
  13. Conforti L, Gilley J, Coleman MP (2014) Wallerian degeneration: an emerging axon death pathway linking injury and disease. Nat Rev Neurosci 15:394-09 CrossRef
  14. Dikranian K, Cohen R, Mac Donald C, Pan Y, Brakefield D, Bayly P et al (2008) Mild traumatic brain injury to the infant mouse causes robust white matter axonal degeneration which precedes apoptotic death of cortical and thalamic neurons. Exp Neurol 211:551-60 CrossRef
  15. Du H, Guo L, Fang F, Chen D, Sosunov AA, McKhann GM et al (2008) Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer’s disease. Nat Med 14:1097-105 CrossRef
  16. Dziedzic T, Metz I, Dallenga T, Konig FB, Muller S, Stadelmann C et al (2010) Wallerian degeneration: a major component of early axonal pathology in multiple sclerosis. Brain Pathol 20:976-85
  17. English AW, Meador W, Carrasco DI (2005) Neu
• 刊物类别：Medicine
• 刊物主题：Medicine & Public Health
  Pathology
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：1432-0533

文摘

Injured axons with distinct morphologies have been found following mild traumatic brain injury (mTBI), although it is currently unclear whether they reflect varied responses to the injury or represent different stages of progressing pathology. This complicates evaluation of therapeutic interventions targeting axonal injury. To address this issue, we assessed axonal injury over time within a well-defined axonal population, while also evaluating mitochondrial permeability transition as a therapeutic target. We utilized mice expressing yellow fluorescent protein (YFP) in cortical neurons which were crossed with mice which lacked Cyclophilin D (CypD), a positive regulator of mitochondrial permeability transition pore opening. Their offspring were subjected to mTBI and the ensuing axonal injury was assessed using YFP expression and amyloid precursor protein (APP) immunohistochemistry, visualized by confocal and electron microscopy. YFP+ axons initially developed a single, APP+, focal swelling (proximal bulb) which progressed to axotomy. Disconnected axonal segments developed either a single bulb (distal bulb) or multiple bulbs (varicosities), which were APP?/sup> and whose ultrastructure was consistent with ongoing Wallerian degeneration. CypD knock-out failed to reduce proximal bulb formation but decreased the number of distal bulbs and varicosities, as well as a population of small, APP+, callosal bulbs not associated with YFP+ axons. The observation that YFP+ axons contain several pathological morphologies points to the complexity of traumatic axonal injury. The fact that CypD knock-out reduced some, but not all, subtypes highlights the need to appropriately characterize injured axons when evaluating potential neuroprotective strategies.