We investigated the potential role of the ubiquitin proteolytic system in the death of cerebellar granule neurons induced by reduction of extracellular potassium. Inhibitors of proteasomal function block apoptosis if administered at onset of this process, but they do not exert such effect when added 2-3 hr later. The same inhibitors also prevent caspase-3 activity and calpain-caspase-3-mediated processing of tau protein, suggesting that proteasomes are involved upstream of the caspase activation. Although the proteasomes seem to play an early primary role in programmed cell death, we found that with progression of apoptosis, during the execution phase, a perturbation in normal ubiquitin-proteasome function occurs, and high levels of ubiquitinated proteins accumulate in the cytoplasm of dying cells. Such accumulation correlates with a progressive decline of proteasome chymotrypsin and trypsinlike activities and, to a lower extent, of postacidic-like activity. Both intracytoplasmic accumulation of ubiquitinated proteins and decline of proteasome function are reversed by the pan-caspase inhibitor Z-VAD-fmk. The decline in proteasome function is accompanied by, and likely attributable to, a marked and progressive decline of deubiquitinating activities. The finding that the proteasomes are early involved in apoptosis and that ubiquitinated proteins accumulate during this process prospect granule neurons as a model system aimed at correlating these events with neurodegenerative diseases.

Canu, N., Barbato, C., Ciotti, M.t., Serafino, A., Dus, L., Calissano, P. (2000). Proteasome involvement and accumulation of ubiquitinated proteins in cerebellar granule neurons undergoing apoptosis. THE JOURNAL OF NEUROSCIENCE, 20(2), 589-599.

Proteasome involvement and accumulation of ubiquitinated proteins in cerebellar granule neurons undergoing apoptosis

CANU, NADIA
;
CALISSANO, PIETRO
2000-01-01

Abstract

We investigated the potential role of the ubiquitin proteolytic system in the death of cerebellar granule neurons induced by reduction of extracellular potassium. Inhibitors of proteasomal function block apoptosis if administered at onset of this process, but they do not exert such effect when added 2-3 hr later. The same inhibitors also prevent caspase-3 activity and calpain-caspase-3-mediated processing of tau protein, suggesting that proteasomes are involved upstream of the caspase activation. Although the proteasomes seem to play an early primary role in programmed cell death, we found that with progression of apoptosis, during the execution phase, a perturbation in normal ubiquitin-proteasome function occurs, and high levels of ubiquitinated proteins accumulate in the cytoplasm of dying cells. Such accumulation correlates with a progressive decline of proteasome chymotrypsin and trypsinlike activities and, to a lower extent, of postacidic-like activity. Both intracytoplasmic accumulation of ubiquitinated proteins and decline of proteasome function are reversed by the pan-caspase inhibitor Z-VAD-fmk. The decline in proteasome function is accompanied by, and likely attributable to, a marked and progressive decline of deubiquitinating activities. The finding that the proteasomes are early involved in apoptosis and that ubiquitinated proteins accumulate during this process prospect granule neurons as a model system aimed at correlating these events with neurodegenerative diseases.
2000
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore BIO/09 - FISIOLOGIA
English
Con Impact Factor ISI
Apoptosis; Cerebellar granule neurons; Deubiquitinating activity; Neurodegeneration; Proteasome activity; Ubiquitin-protein conjugates
caspase; proteasome; tau protein; ubiquitin; animal cell; apoptosis; article; cell death; cerebellum cortex; enzyme activation; enzyme activity; granule cell; morphogenesis; nerve cell plasticity; nerve degeneration; nonhuman; priority journal; protein analysis; protein degradation; protein processing; rat; transcription regulation; Acetylcysteine; Animals; Apoptosis; Cell Division; Cell Survival; Cells, Cultured; Cerebellum; Culture Media, Serum-Free; Cysteine Endopeptidases; Cysteine Proteinase Inhibitors; Leucine; Leupeptins; Multienzyme Complexes; Neurons; Oligopeptides; Proteasome Endopeptidase Complex; Protein Processing, Post-Translational; Rats; Rats, Wistar; Ubiquitins
Canu, N., Barbato, C., Ciotti, M.t., Serafino, A., Dus, L., Calissano, P. (2000). Proteasome involvement and accumulation of ubiquitinated proteins in cerebellar granule neurons undergoing apoptosis. THE JOURNAL OF NEUROSCIENCE, 20(2), 589-599.
Canu, N; Barbato, C; Ciotti, Mt; Serafino, A; Dus, L; Calissano, P
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/56959
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