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The Journal of Neuroscience, October 1, 2000, 20(19):7345-7352
The Human DIMINUTO/DWARF1 Homolog Seladin-1 Confers
Resistance to Alzheimer's Disease-Associated Neurodegeneration and
Oxidative Stress
Isabell
Greeve1,
Irm
Hermans-Borgmeyer1,
Claire
Brellinger1,
Dagmar
Kasper1,
Teresa
Gomez-Isla2,
Christian
Behl3,
Bodo
Levkau4, and
Roger M.
Nitsch5
1 Center for Molecular Neurobiology Hamburg, University
of Hamburg, 20246 Hamburg, Germany, 2 Department of
Neurology, Clinica Universitaria de Navarra, Pamplona 31008, Navarra,
Spain, 3 Max Planck Institute for Psychiatry, 80804 Munich,
Germany, 4 Institute for Arteriosclerosis Research,
University of Münster, 48149 Münster, Germany, and
5 Division of Psychiatry Research, University of Zurich,
8008 Zurich, Switzerland
In Alzheimer's disease (AD) brains, selected populations of
neurons degenerate heavily, whereas others are frequently spared from
degeneration. To address the cellular basis for this selective vulnerability of neurons in distinct brain regions, we compared gene
expression between the severely affected inferior temporal lobes and
the mostly unaffected fronto-parietal cortices by using an mRNA
differential display. We identified seladin-1, a novel gene, which was downregulated in large pyramidal neurons in vulnerable regions in AD but not control brains. Seladin-1 is a human
homolog of the DIMINUTO/DWARF1 gene described in plants
and Caenorhabditis elegans. Its sequence shares
similarities with flavin-adenin-dinucleotide (FAD)-dependent
oxidoreductases. In human control brain, seladin-1 was highly expressed in almost all neurons. In PC12 cell clones that were selected for resistance against AD-associated amyloid- peptide (A)-induced toxicity, both mRNA and protein levels of seladin-1 were approximately threefold higher as compared with the
non-resistant wild-type cells. Functional expression of seladin-1 in
human neuroglioma H4 cells resulted in the inhibition of caspase 3 activation after either A-mediated toxicity or oxidative stress and
protected the cells from apoptotic cell death. In apoptotic cells,
however, endogenous seladin-1 was cleaved to a 40 kDa derivative in a
caspase-dependent manner. These results establish that seladin-1 is an
important factor for the protection of cells against A toxicity and
oxidative stress, and they suggest that seladin-1 may be involved in
the regulation of cell survival and death. Decreased expression of
seladin-1 in specific neurons may be a cause for selective
vulnerability in AD.
Key words:
Alzheimer's disease; neurodegeneration; -amyloid; seladin-1; human DIMINUTO/DWARF1 homolog; oxidative stress; differential display
Copyright © 2000 Society for Neuroscience 0270-6474/00/20197345-08$05.00/0
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