Cellular Zn2+ chelators cause dying-back neurite degeneration associated with energy impairment

Most cellular zinc is tightly associated with metalloproteins and other Zn2+-dependent proteins, which along with cellular Zn2+ compartments may coordinately regulate cytoplasmic free Zn2+ levels in the picomolar range. Moreover, Zn2+ -containing endosomes or protein complexes appear to move along axons or dendrites, suggesting a dynamic mechanism for trafficking, exchanging, or scavenging Zn2+ and/or Zn2+ protein complexes in neurons. It is therefore interesting to examine whether cellular Zn2+ levels might alter neurite integrity and dynamics. Here we show that membrane-permeable zinc chelators, including 1,10-phenan-throline, N,N,N',N'-tetrakis-(2-pyridylmethyl)-ethylenediamine (TPEN), and zinquin, selectively elicit axon and dendrite degeneration but leave the cell body intact in sympathetic neurons. The process begins distally and then moves retrogradely, with a distinct dying-back pattern. An inactive isomer of 1,10-phenanthroline failed to cause neuite degeneration, and these chelators mediated their effects by selectively chelating Zn-2 divided by, but not other metals. Moreover, neurite degeneration was associated with a decrease in neuritic ATP levels and was caused by energy failure, because an exogenous supply of nicotinamide adenine dinucleotide (NAD) or its precursor nicotinamide suppressed the degeneration by delaying axonal ATP reduction caused. by Zn-2 divided by depletion. Blockage of autophagy by 3-methyl-adenine provided partial protection against degeneration of terminal axons or dendrites; there was, however, no obvious alteration in that of medial portions. Collectively, our results show that cellular Zn2+ depletion induces a dying-back degeneration characterized by an NAD- and autophagy-depenclent process, independently of neurite elongation dynamics. (c) 2007 Wiley-Liss, Inc.