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Published 14 February 2005. doi:10.1083/jcb.200406126
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 168, Number 4, 607-618
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Article

Botulinum neurotoxin C initiates two different programs for neurite degeneration and neuronal apoptosis



Laura Berliocchi1, Eugenio Fava1, Marcel Leist2, Volker Horvat3, David Dinsdale1, David Read1, and Pierluigi Nicotera1

1 Medical Research Council Toxicology Unit, Leicester LE2 3HD, UK
2 Disease Biology, H. Lundbeck A/S, DK-2500 Valby, Denmark
3 Max-Delbrück-Zentrum für Molekulare Medizin, 13092 Berlin, Germany

Correspondence to Pierluigi Nicotera: pn10{at}le.ac.uk

Clostridial neurotoxins are bacterial endopeptidases that cleave the major SNARE proteins in peripheral motorneurons. Here, we show that disruption of synaptic architecture by botulinum neurotoxin C1 (BoNT/C) in central nervous system neurons activates distinct neurodegenerative programs in the axo-dendritic network and in the cell bodies. Neurites degenerate at an early stage by an active caspase-independent fragmentation characterized by segregation of energy competent mitochondria. Later, the cell body mitochondria release cytochrome c, which is followed by caspase activation, apoptotic nuclear condensation, loss of membrane potential, and, finally, cell swelling and lysis. Recognition and scavenging of dying processes by glia also precede the removal of apoptotic cell bodies, in line with a temporal and spatial segregation of different degenerative processes. Our results suggest that, in response to widespread synaptic damage, neurons first dismantle their connections and finally undergo apoptosis, when their spatial relationships are lost.

Abbreviations used in this paper: afc, aminotrifluoromethylcoumarine; BoNT/C/A, botulinum neurotoxin C1 or A; CGC, cerebellar granule cell; fmk, fluoromethylketone; HMM, high molecular mass; mtHSP-70, mitochondrial heat-shocked protein 70; TMRE, tetramethylrhodamine ethyl ester.

E. Fava's present address is Max-Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.


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