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The Journal of Neuroscience, January 15, 2000, 20(2):589-599

Proteasome Involvement and Accumulation of Ubiquitinated Proteins in Cerebellar Granule Neurons Undergoing Apoptosis

Nadia Canu¹, Christian Barbato¹, Maria Teresa Ciotti², Annalucia Serafino³, Laura Dus², and Pietro Calissano^{1, 2}

¹ Dipartimento di Neuroscienze, Facoltà di Medicina e Chirurgia, Università di Tor Vergata, 00133 Roma, Italia, ² Istituto di Neurobiologia, Consiglio Nazionale delle Ricerche (CNR), 00137 Roma, Italia, and ³ Area di Ricerca di Roma, Tor Vergata, CNR, 00133 Roma, Italia

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 trypsin-like 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.

Key words: apoptosis; neurodegeneration; ubiquitin-protein conjugates; proteasome activity; deubiquitinating activity; cerebellar granule neurons

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Copyright © 2000 Society for Neuroscience  0270-6474/00/202589-11$05.00/0

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