Autophagic neuron death.

Abstract

Neurons of the central nervous system (CNS) tissue are terminally differentiated cells and have large volumes, unlike cells of peripheral tissues. Such neurons possess abundant lysosomes in which damaged and unneeded intracellular constituents are degraded. A cellular process to bring the unneeded constituents to lysosomes is referred to as macroautophagy (autophagy), which is essential for the maintenance of cellular metabolism under physiological conditions. In fact, mice deficient in Atg7 or Atg5 specifically in CNS tissue have ubiquitin aggregates in neurons and massive loss of cerebral and cerebellar cortical neurons, resulting in neurodegeneration and short life span. In addition, acceleration of autophagy induced by the loss of lysosomal proteinases such as cathepsin D or cathepsins B and L, or by hypoxic/ischemic (H/I) brain injury, causes neurodegeneration. Moreover, lysosomes with undigested materials due to loss of proteinases are enwrapped by double membranes to produce autophagosomes, resulting in the further accumulation of autolysosomes. H/I brain injury at birth that is an important cause of cerebral palsy, mental retardation, and epilepsy causes energy failure, oxidative stress, and unbalanced ion fluxes, leading to a high induction of autophagy in brain neurons. Since mice that are unable to execute autophagy (due to brain-specific deletion of Atg7 or Atg5) die as a result of massive loss of cerebral and cerebellar neurons with accumulation of ubiquitin aggregates, induction of neuronal autophagy after H/I injury is generally considered neuroprotective, as it maintains cellular homeostasis. However, our data showing that H/I injury-induced pyramidal neuron death in the neonatal hippocampus is largely prevented by Atg7 deficiency indicate the presence of autophagic neuron death. In this section, we introduce various methods for the detection of autophagic neuron death in addition to other death modes of CNS neurons.

• Authors: Yasuo Uchiyama, Masato Koike, Masahiro Shibata, Mitsuho Sasaki
• Journal: Methods in enzymology (Methods Enzymol) Vol. 453 Pg. 33-51 ( 2009) ISSN: 1557-7988 [Electronic] United States
• PMID: 19216901 (Publication Type: Journal Article)

Chemical References

• Cathepsin B

Topics

• Animals
• Autophagy (physiology)
• Blotting, Western
• Brain (metabolism, pathology)
• Cathepsin B (metabolism)
• Mice
• Mice, Inbred C57BL
• Microscopy, Confocal
• Microscopy, Electron
• Neurons (cytology, metabolism)
• PC12 Cells
• Rats
• Rats, Wistar