Abstract
Stroke is the leading cause of disability in developed countries. However, no treatment is available beyond 3 h post-ictus. Here, we report that nuclear translocation of PTEN (phosphatase and tensin homolog deleted on chromosome TEN) is a delayed step causatively leading to excitotoxic (in vitro) and ischemic (in vivo) neuronal injuries. We found that excitotoxic stimulation of N-methyl-d-aspartate (NMDA) resulted in PTEN nuclear translocation in cultured neurons, a process requiring mono-ubiquitination at the lysine 13 residue (K13), as the translocation was prevented by mutation of K13 or a short interfering peptide (Tat-K13) that flanks the K13 residue. More importantly, using a rat model of focal ischemia, we demonstrated that systemic application of Tat-K13, even 6 h after stroke, not only reduced ischemia-induced PTEN nuclear translocation, but also strongly protected against ischemic brain damage. Our study suggests that inhibition of PTEN nuclear translocation may represent a novel after stroke therapy.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Brain / cytology
-
Brain Ischemia / complications
-
Brain Ischemia / diagnostic imaging
-
Brain Ischemia / metabolism*
-
Cells, Cultured
-
Disease Models, Animal
-
Embryo, Mammalian
-
Excitatory Amino Acid Agonists / toxicity
-
Female
-
Fluorodeoxyglucose F18
-
Green Fluorescent Proteins / genetics
-
Green Fluorescent Proteins / metabolism
-
L-Lactate Dehydrogenase / metabolism
-
Male
-
Mice
-
Mutation / genetics
-
N-Methylaspartate / toxicity
-
Nervous System Diseases / etiology
-
Neurons / drug effects
-
Neurons / metabolism*
-
Nuclear Localization Signals / genetics
-
Nuclear Localization Signals / metabolism
-
PTEN Phosphohydrolase / genetics
-
PTEN Phosphohydrolase / metabolism*
-
Peptides / metabolism
-
Pregnancy
-
Protein Transport / drug effects
-
Protein Transport / physiology
-
Radionuclide Imaging
-
Rats
-
Rats, Sprague-Dawley
Substances
-
Excitatory Amino Acid Agonists
-
Nuclear Localization Signals
-
Peptides
-
enhanced green fluorescent protein
-
Fluorodeoxyglucose F18
-
Green Fluorescent Proteins
-
N-Methylaspartate
-
L-Lactate Dehydrogenase
-
PTEN Phosphohydrolase