The human DIMINUTO/DWARF1 homolog seladin-1 confers resistance to Alzheimer's disease-associated neurodegeneration and oxidative stress.
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-beta peptide (Abeta)-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 Abeta-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 Abeta 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.
Greeve
I
I
Center for Molecular Neurobiology Hamburg, University of Hamburg, 20246 Hamburg, Germany. isabell.greeve@zmnh.uni-hamburg.de
Hermans-Borgmeyer
I
I
Brellinger
C
C
Kasper
D
D
Gomez-Isla
T
T
Behl
C
C
Levkau
B
B
Nitsch
R M
RM
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D029681:Arabidopsis Proteins; D001921:Brain / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3; D061945:Caspase Inhibitors; D015536:Down-Regulation / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D005910:Glioma / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009928:Organ Specificity; D018384:Oxidative Stress; D044925:Oxidoreductases Acting on CH-CH Group Donors; D016716:PC12 Cells; D010940:Plant Proteins / Q000235:genetics*; D017966:Pyramidal Cells / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017386:Sequence Homology, Amino Acid; D014407:Tumor Cells, Cultured
D016229:Amyloid beta-Peptides; D029681:Arabidopsis Proteins; D061945:Caspase Inhibitors; C091574:DIM1 protein, Arabidopsis; D009419:Nerve Tissue Proteins; D010940:Plant Proteins; D012333:RNA, Messenger; D044925:Oxidoreductases Acting on CH-CH Group Donors; C437069:3beta-hydroxysterol delta24-reductase; C499055:DHCR24 protein, human; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3