Type

Journal Article

Authors

Jochen H M Prehn
Caoimhín G Concannon
David C Henshall
Waro Taki
Manus W Ward
Satoshi Matsushima
Ina Woods
Tobias Engel
Helena P Bonner
Takuro Tsuchiya

Subjects

Biochemistry

Topics
proteasome inhibitors immunohistochemistry puma protein mouse apoptosis membrane proteins animals bcl 2 like protein 11 mice proto oncogene proteins tumor suppressor proteins drug effects mice knockout reverse transcriptase polymerase chain reaction hippocampus in situ nick end labeling genetics metabolism toxicity neurons pathology mice inbred c57bl blotting western apoptosis regulatory proteins physiology oligopeptides epoxomicin

Bcl-2 homology domain 3-only proteins Puma and Bim mediate the vulnerability of CA1 hippocampal neurons to proteasome inhibition in vivo. (2010)

Abstract Bcl-2 homology domain 3 (BH3)-only proteins are pro-apoptotic Bcl-2 family members that play important roles in upstream cell death signalling during apoptosis. Proteasomal stress has been shown to contribute to the pathology of cerebral ischaemia and many neurodegenerative disorders. Here we explored the contribution of BH3-only proteins in mediating proteasome-inhibition-induced apoptosis in the murine brain in vivo. Stereotactic intrahippocampal microinjection of the selective proteasome inhibitor epoxomicin (2.5 nmol) induced a delayed apoptosis within only the CA1 hippocampal neurons and not neurons within the CA3 or dentate gyrus regions, a selective vulnerability similar to that seen during ischaemia. This injury developed over a time-course of 3 days and was characterized by positive terminal deoxynucleotidyl transferase dUTP nick end labelling staining and nuclear condensation. Previous work from our laboratory has identified the BH3-only protein p53-upregulated mediator of apoptosis (Puma) as mediating proteasome-inhibition-induced apoptosis in cultured neural cells. Genetic deletion of puma reduced the number of terminal deoxynucleotidyl transferase dUTP nick end labelling-positive cells within the CA1 following epoxomicin microinjection but it did not provide a complete protection. Subsequent studies identified the BH3-only protein Bim as also being upregulated during proteasome inhibition in organotypic hippocampal slice cultures and after epoxomicin treatment in vivo. Interestingly, the genetic deletion of bim also afforded significant neuroprotection, although this protection was less pronounced. In summary, we demonstrate that the BH3-only proteins Puma and Bim mediate the delayed apoptosis of CA1 hippocampal neurons induced by proteasome inhibition in vivo, and that either BH3-only protein can only partly compensate for the deficiency of the other.
Collections Ireland -> Royal College of Surgeons in Ireland -> PubMed

Full list of authors on original publication

Jochen H M Prehn, Caoimhín G Concannon, David C Henshall, Waro Taki, Manus W Ward, Satoshi Matsushima, Ina Woods, Tobias Engel, Helena P Bonner, Takuro Tsuchiya

Experts in our system

1
Jochen H M Prehn
Royal College of Surgeons in Ireland
Total Publications: 206
 
2
Caoimhín G Concannon
Royal College of Surgeons in Ireland
Total Publications: 46
 
3
David C Henshall
Royal College of Surgeons in Ireland
Total Publications: 127
 
4
Ina Woods
Royal College of Surgeons in Ireland
Total Publications: 16
 
5
Tobias Engel
Royal College of Surgeons in Ireland
Total Publications: 66
 
6
Helena P Bonner
Royal College of Surgeons in Ireland
Total Publications: 15