Convergence of stress granules and protein aggregates in hippocampal cornu ammonis 1 at later reperfusion following global brain ischemia.
The delayed and selective vulnerability of post-ischemic hippocampal cornu ammonis (CA) 1 pyramidal neurons correlates with a lack of recovery of normal protein synthesis. Recent evidence implicates sequestration of translational machinery into protein aggregates and stress granules as factors underlying persistent translation arrest in CA1 neurons. However, the relationship between protein aggregates and stress granules during brain reperfusion is unknown. Here we investigated the colocalization of protein aggregates and stress granules using immunofluorescence microscopy and pair-wise double labeling for ubiquitin/T cell internal antigen (TIA-1), ubiquitin/small ribosomal subunit protein 6 (S6), and TIA-1/S6. We evaluated the rat dorsal hippocampus at 1, 2 or 3 days of reperfusion following a 10 min global brain ischemic insult. At 1 day of reperfusion, ubiquitin-containing aggregates (ubi-protein clusters) occurred in neurons but did not colocalize with stress granules. At 2 days' reperfusion, only in CA1, cytoplasmic protein aggregates colocalized with stress granules, and ubiquitin-containing inclusions accumulated in the nuclei of CA1 pyramidal neurons. Functionally, a convergence of stress granules and protein aggregates would be expected to sustain translation arrest and inhibit clearance of ubiquitinated proteins, both factors expected to contribute to CA1 pyramidal neuron vulnerability.
DeGracia
D J
DJ
Department of Physiology, Wayne State University School of Medicine, 4116 Scott Hall, 540 East Canfield Avenue, Detroit, MI 48201, USA. ddegraci@med.wayne.edu
Rudolph
J
J
Roberts
G G
GG
Rafols
J A
JA
Wang
J
J
D000704:Analysis of Variance; D000818:Animals; D002545:Brain Ischemia / Q000473:pathology*; D002452:Cell Count; D016923:Cell Death; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology*; D002479:Inclusion Bodies / Q000473:pathology*; D008297:Male; D014176:Protein Biosynthesis / Q000502:physiology; D017966:Pyramidal Cells / Q000378:metabolism / Q000473:pathology*; D016601:RNA-Binding Proteins / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D015424:Reperfusion / Q000379:methods*; D038601:Ribosomal Protein S6 / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism / Q000473:pathology; D025801:Ubiquitin / Q000378:metabolism
D016601:RNA-Binding Proteins; D038601:Ribosomal Protein S6; C489666:Tial1 protein, rat; D025801:Ubiquitin