Hypoxic ischemia and proteasome dysfunction alter tau isoform ratio by inhibiting exon 10 splicing.
Alternative splicing of tau exon 10 influences microtubule assembly and stability during development and in pathological processes of the central nervous system. However, the cellular events that underlie this pre-mRNA splicing remain to be delineated. In this study, we examined the possibility that ischemic injury, known to change the cellular distribution and expression of several RNA splicing factors, alters the splicing of tau exon 10. Transient occlusion of the middle cerebral artery reduced tau exon 10 inclusion in the ischemic cortical area within 12 h, resulting in the induction of three-repeat (3R) tau in cortical neurons. Ubiquitinated protein aggregates and reduced proteasome activity were also observed. Administration of proteasome inhibitors such as MG132, proteasome inhibitor I and lactacystin reduced tau exon 10 splicing in cortical cell cultures. Decreased levels of Tra2beta, an RNA splicing factor responsible for tau exon 10 inclusion, were detected both in cortical cell cultures exposed to MG132 and in cerebral cortex after ischemic injury. Taken together, these findings suggest that transient focal cerebral ischemia reduces tau exon 10 splicing through a mechanism involving proteasome-ubiquitin dysfunction and down-regulation of Tra2beta.
Suh
Jaehong
J
Department of Pharmacology, Ajou University School of Medicine, Suwon 442-749, Korea.
Im
Doo Soon
DS
Moon
Gyeong Joon
GJ
Ryu
Keun Sil
KS
de Silva
Rohan
R
Choi
In Sun
IS
Lees
Andrew J
AJ
Guénette
Suzanne Y
SY
Tanzi
Rudolph E
RE
Gwag
Byoung Joo
BJ
D017398:Alternative Splicing; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism; D005091:Exons; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism*; D002546:Ischemic Attack, Transient / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000502:physiology*; D061988:Proteasome Inhibitors; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068103:Serine-Arginine Splicing Factors; D054875:Ubiquitination; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
D009687:Nuclear Proteins; D061988:Proteasome Inhibitors; D020033:Protein Isoforms; D016601:RNA-Binding Proteins; D016875:tau Proteins; D000068103:Serine-Arginine Splicing Factors; D046988:Proteasome Endopeptidase Complex