Type

Journal Article

Authors

Jochen H M Prehn
Manus W Ward
Heinrich J Huber
Ina Woods
Matthew A King
Beatrice D'Orsi
Caoimhín G Concannon
Liam P Tuffy

Subjects

Biochemistry

Topics
metabolism models neurological bh3 interacting domain death agonist protein pmaip1 protein mouse gene expression stress physiological mice knockout genetics nerve degeneration mice inbred c57bl apoptosis regulatory proteins neurons protease inhibitors autophagy bid protein mouse rna small interfering deficiency proteasome inhibitors pathology physiology pharmacology casp3 protein mouse puma protein mouse proto oncogene proteins c bcl 2 caspase 3 animals dna primers base sequence bcl 2 like protein 11 cathepsins fluorescence resonance energy transfer apoptosis membrane proteins mice proto oncogene proteins cytochromes c cytology drug effects tumor suppressor proteins lysosomes membrane potential mitochondrial

Characterization of Puma-dependent and Puma-independent neuronal cell death pathways following prolonged proteasomal inhibition. (2010)

Abstract Proteasomal stress and the accumulation of polyubiquitinated proteins are key features of numerous neurodegenerative disorders. Previously we demonstrated that stabilization of p53 and activation of its target gene, puma (p53-upregulated mediator of apoptosis), mediated proteasome inhibitor-induced apoptosis in cancer cells. Here we demonstrated that Puma also contributed to proteasome inhibitor-induced apoptosis in mouse neocortical neurons. Although protection afforded by puma gene deletion was incomplete, we found little evidence indicating contributions from other proapoptotic BH3-only proteins. Attenuation of bax expression did not further reduce Puma-independent apoptosis, suggesting that pathways other than the mitochondrial apoptosis pathway were activated. Real-time imaging experiments in wild-type and puma-deficient neurons using a fluorescence resonance energy transfer (FRET)-based caspase sensor confirmed the involvement of a second cell death pathway characterized by caspase activation prior to mitochondrial permeabilization and, more prominently, a third, caspase-independent and Puma-independent pathway characterized by rapid cell shrinkage and nuclear condensation. This pathway involved lysosomal permeabilization in the absence of autophagy activation and was sensitive to cathepsin but not autophagy inhibition. Our data demonstrate that proteasomal stress activates distinct cell death pathways in neurons, leading to both caspase-dependent and caspase-independent apoptosis, and demonstrate independent roles for Puma and lysosomal permeabilization in this model.
Collections Ireland -> Royal College of Surgeons in Ireland -> PubMed

Full list of authors on original publication

Jochen H M Prehn, Manus W Ward, Heinrich J Huber, Ina Woods, Matthew A King, Beatrice D'Orsi, Caoimhín G Concannon, Liam P Tuffy

Experts in our system

1
Jochen H M Prehn
Royal College of Surgeons in Ireland
Total Publications: 206
 
2
Heinrich J Huber
Royal College of Surgeons in Ireland
Total Publications: 39
 
3
Ina Woods
Royal College of Surgeons in Ireland
Total Publications: 16
 
4
Beatrice D'Orsi
Royal College of Surgeons in Ireland
Total Publications: 14
 
5
Caoimhín G Concannon
Royal College of Surgeons in Ireland
Total Publications: 46
 
6
Liam P Tuffy
Royal College of Surgeons in Ireland
Total Publications: 13