Editors' ChoiceNeuroscience

Death Fragment

Science Signaling  24 Feb 2009:
Vol. 2, Issue 59, pp. ec67
DOI: 10.1126/scisignal.259ec67

During development of the nervous system, cell death mechanisms remove inappropriate neurons and axon branches, leaving viable connections in place (see Nicholson); however, neuronal death and axonal degeneration also occur in neurodegenerative diseases. Cell death may be either passive, through the loss of neurotrophic factors, or active, mediated by receptors such as tumor necrosis factor receptor family members. Nikolaev et al. found that one such receptor, DR6 (considered an orphan), was more abundant on differentiating neurons than on progenitor cells. Loss of DR6 or antibody-mediated blocking of DR6 protected mouse spinal neurons from death caused by trophic depletion in vitro. Culture of neurons in compartmented chambers showed that DR6 was required for neuronal death and axonal degeneration; however, whereas death of cell bodies was mediated by caspase-3 (as previously shown), axonal degeneration (which was thought to be caspase-independent) was mediated by the nonclassical effector caspase-6. A fusion of the DR6 ectodomain to human Fc bound to the membranes of healthy, but not deprived, sensory and motor axons in culture, and a DR6-binding protein was detected in the medium of deprived, but not healthy, neurons. Deprivation of neurons in culture triggered the cleavage of amyloid precursor protein (APP) to produce a fragment (N-APP), which bound to DR6 with high affinity. Degeneration of neurons in response to trophic deprivation was blocked by an antibody against N-APP, and knockdown of App reduced death in response to trophic withdrawal compared with that in control neurons. Finally, DR6-deficient and App-deficient mice showed a similar axonal-pruning defect at the neuromuscular junction. Together, these data suggest that APP and DR6 mediate neuronal death and axonal degeneration (through distinct caspases) after trophic deprivation.

A. Nikolaev, T. McLaughlin, D. D. M. O’Leary, M. Tessier-Lavigne, APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature 457, 981–989 (2009). [PubMed]

D. W. Nicholson, Good and bad cell death. Nature 457, 970–971 (2009). [PubMed]