Botulinum neurotoxin C initiates two different programs for neurite degeneration and neuronal apoptosis.
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.
Berliocchi
Laura
L
Medical Research Council Toxicology Unit, Leicester LE2 3HD, UK.
Fava
Eugenio
E
Leist
Marcel
M
Horvat
Volker
V
Dinsdale
David
D
Read
David
D
Nicotera
Pierluigi
P
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001905:Botulinum Toxins / Q000633:toxicity*; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D045304:Cytochromes c / Q000378:metabolism; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008855:Microscopy, Electron, Scanning; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016501:Neurites; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000378:metabolism
D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; D045304:Cytochromes c; D001905:Botulinum Toxins; C096324:botulinum toxin type C
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