Nedd4-WW domain-binding protein 5 (Ndfip1) is associated with neuronal survival after acute cortical brain injury.
Understanding the transcriptional response to neuronal injury after trauma is a necessary prelude to formulation of therapeutic strategies. We used Serial Analysis of Gene Expression (SAGE) to identify 50,000 sequence tags representing 18,000 expressed genes in the cortex 2 h after traumatic brain injury (TBI). A similar tag library was obtained from sham-operated cortex. The SAGE data were validated on biological replicates using quantitative real-time-PCR on multiple samples at 2, 6, 12, and 24 h after TBI. This analysis revealed that the vast majority of genes showed a downward trend in their pattern of expression over 24 h. This was confirmed for a subset of genes using in situ hybridization and immunocytochemistry on brain sections. Of the overexpressed genes in the trauma library, Nedd4-WW (neural precursor cell expressed, developmentally downregulated) domain-binding protein 5 (N4WBP5) (also known as Ndfip1) is strongly expressed in surviving neurons around the site of injury. Overexpression of N4WBP5 in cultured cortical neurons increased the number of surviving neurons after gene transfection and growth factor starvation compared with control transfections. These results identify N4WBP5 as a neuroprotective protein and, based on its known interaction with the ubiquitin ligase Nedd4, would suggest protein ubiquitination as a possible survival strategy in neuronal injury.
Sang
Qian
Q
Howard Florey Institute, The University of Melbourne, Parkville, Victoria 3010, Australia.
Kim
Mary H
MH
Kumar
Sharad
S
Bye
Nicole
N
Morganti-Kossman
Maria C
MC
Gunnersen
Jenny
J
Fuller
Stephanie
S
Howitt
Jason
J
Hyde
Lavinia
L
Beissbarth
Tim
T
Scott
Hamish S
HS
Silke
John
J
Tan
Seong-Seng
SS
D000208:Acute Disease; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001930:Brain Injuries / Q000473:pathology / Q000503:physiopathology*; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002540:Cerebral Cortex / Q000293:injuries / Q000473:pathology / Q000503:physiopathology; D020869:Gene Expression Profiling; D015723:Gene Library; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009414:Nerve Growth Factors / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025801:Ubiquitin / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
D002352:Carrier Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C499188:Ndfip1 protein, mouse; D009414:Nerve Growth Factors; D025801:Ubiquitin