Cellular Zn(2+) chelators cause "dying-back" neurite degeneration associated with energy impairment. Export

@article{citeulike:1476858, abstract = {Most cellular zinc is tightly associated with metalloproteins and other Zn(2+)-dependent proteins, which along with cellular Zn(2+) compartments may coordinately regulate cytoplasmic free Zn(2+) levels in the picomolar range. Moreover, Zn(2+)-containing endosomes or protein complexes appear to move along axons or dendrites, suggesting a dynamic mechanism for trafficking, exchanging, or scavenging Zn(2+) and/or Zn(2+) protein complexes in neurons. It is therefore interesting to examine whether cellular Zn(2+) levels might alter neurite integrity and dynamics. Here we show that membrane-permeable zinc chelators, including 1,10-phenanthroline, 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+), 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+) depletion. Blockage of autophagy by 3-methyladenine 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 Zn(2+) depletion induces a "dying-back" degeneration characterized by an NAD- and autophagy-dependent process, independently of neurite elongation dynamics. (c) 2007 Wiley-Liss, Inc.}, address = {Molecular Neurobiology Laboratory, Division of Life Science, Graduate School of Life Science, Hokkaido University, Sapporo, Japan.}, author = {Yang, Yi and Kawataki, Taku and Fukui, Koji and Koike, Tatsuro}, citeulike-article-id = {1476858}, citeulike-linkout-0 = {http://dx.doi.org/10.1002/jnr.21411}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/17628505}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=17628505}, comment = {Important Points: a) Claims that the cultures includeed both dendrites and axons and that both exhibited the same dying back degeneration independent of cell body apoptosis. b) More support for the NAD hypothesis of Wlds neuroprotection}, day = {12}, doi = {10.1002/jnr.21411}, issn = {0360-4012}, journal = {J Neurosci Res}, keywords = {atp, axons, degeneration, dendrite, dying-back, mechanism, neurite, zn}, month = {July}, posted-at = {2007-07-24 14:34:34}, priority = {0}, title = {Cellular Zn(2+) chelators cause "dying-back" neurite degeneration associated with energy impairment.}, url = {http://dx.doi.org/10.1002/jnr.21411}, year = {2007} }

TY - JOUR ID - citeulike:1476858 L3 - citeulike-article-id:1476858 N2 - Most cellular zinc is tightly associated with metalloproteins and other Zn(2+)-dependent proteins, which along with cellular Zn(2+) compartments may coordinately regulate cytoplasmic free Zn(2+) levels in the picomolar range. Moreover, Zn(2+)-containing endosomes or protein complexes appear to move along axons or dendrites, suggesting a dynamic mechanism for trafficking, exchanging, or scavenging Zn(2+) and/or Zn(2+) protein complexes in neurons. It is therefore interesting to examine whether cellular Zn(2+) levels might alter neurite integrity and dynamics. Here we show that membrane-permeable zinc chelators, including 1,10-phenanthroline, 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+), 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+) depletion. Blockage of autophagy by 3-methyladenine 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 Zn(2+) depletion induces a "dying-back" degeneration characterized by an NAD- and autophagy-dependent process, independently of neurite elongation dynamics. (c) 2007 Wiley-Liss, Inc. JF - J Neurosci Res SN - 0360-4012 AD - Molecular Neurobiology Laboratory, Division of Life Science, Graduate School of Life Science, Hokkaido University, Sapporo, Japan. TI - Cellular Zn(2+) chelators cause "dying-back" neurite degeneration associated with energy impairment. KW - atp KW - axons KW - degeneration KW - dendrite KW - dying-back KW - mechanism KW - neurite KW - zn N1 - Important Points: a) Claims that the cultures includeed both dendrites and axons and that both exhibited the same dying back degeneration independent of cell body apoptosis. b) More support for the NAD hypothesis of Wlds neuroprotection AU - Yang, Yi AU - Kawataki, Taku AU - Fukui, Koji AU - Koike, Tatsuro PY - 2007/07/12/ UR - http://dx.doi.org/10.1002/jnr.21411 ER -