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The human DIMINUTO/DWARF1 homolog seladin-1 confers resistance to Alzheimer's disease-associated neurodegeneration and oxidative stress.
- Source :
-
The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2000 Oct 01; Vol. 20 (19), pp. 7345-52. - Publication Year :
- 2000
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Abstract
- 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.
- Subjects :
- Aged
Aged, 80 and over
Alzheimer Disease metabolism
Alzheimer Disease pathology
Amyloid beta-Peptides pharmacology
Animals
Apoptosis drug effects
Apoptosis genetics
Brain metabolism
Brain pathology
Caspase 3
Caspase Inhibitors
Down-Regulation genetics
Endoplasmic Reticulum metabolism
Female
Gene Expression Profiling
Glioma metabolism
Humans
Male
Middle Aged
Molecular Sequence Data
Nerve Tissue Proteins genetics
Organ Specificity
PC12 Cells
Pyramidal Cells metabolism
Pyramidal Cells pathology
RNA, Messenger biosynthesis
Rats
Tumor Cells, Cultured
Alzheimer Disease genetics
Arabidopsis Proteins
Nerve Tissue Proteins metabolism
Oxidative Stress
Oxidoreductases Acting on CH-CH Group Donors
Plant Proteins genetics
Sequence Homology, Amino Acid
Subjects
Details
- Language :
- English
- ISSN :
- 1529-2401
- Volume :
- 20
- Issue :
- 19
- Database :
- MEDLINE
- Journal :
- The Journal of neuroscience : the official journal of the Society for Neuroscience
- Publication Type :
- Academic Journal
- Accession number :
- 11007892