Autophagy and protein aggregation after brain ischemia.
Autophagy is the main degradation pathway responsible for eliminating abnormal protein aggregates and damaged organelles prevalent in neurons after transient cerebral ischemia. This study investigated whether accumulation of protein aggregate-associated organelles in post-ischemic neurons is a consequence of changes in autophagy. Electron microscopic analysis indicated that both autophagosomes and autolysosomes are significantly up-regulated in hippocampal CA1 and DG neurons after ischemia. The microtubule-associated protein light chain 3 (LC3)-II conjugate, a marker for autophagosomes assessed by western blotting, was up-regulated in post-ischemic brain tissues. Confocal microscopy showed that LC3 isoforms were located in living post-ischemic neurons. Treatment with chloriquine resulted in accumulation of LC3-II in sham-operated rats, but did not further change the LC3-II levels in post-ischemic brain tissues. The results indicate that at least part of the accumulation of protein aggregate-associated organelles seen following ischemia is likely to be because of failure of the autophagy pathway. The resulting protein aggregation on subcellular organelle membranes could lead to multiple organelle damage and to delayed neuronal death after transient cerebral ischemia.
Liu
Chunli
C
Department of Neurology, University of Miami School of Medicine, Miami, Florida 33136, USA.
Gao
Yanqin
Y
Barrett
John
J
Hu
Bingren
B
D000818:Animals; D001343:Autophagy / Q000502:physiology*; D015153:Blotting, Western; D001921:Brain / Q000473:pathology; D002545:Brain Ischemia / Q000473:pathology*; D016923:Cell Death / Q000502:physiology; D007150:Immunohistochemistry; D008247:Lysosomes / Q000187:drug effects; D008297:Male; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D015388:Organelles / Q000502:physiology / Q000648:ultrastructure; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology; D013347:Subcellular Fractions / Q000378:metabolism / Q000648:ultrastructure; D015854:Up-Regulation / Q000502:physiology
D009419:Nerve Tissue Proteins