The Human DIMINUTO/DWARF1 Homolog Seladin-1 Confers Resistance to Alzheimer's Disease-Associated Neurodegeneration and Oxidative Stress

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.

Seladin-1 as a target of estrogen receptor activation in the brain: A new gene for a rather old story?

“…In 2000, Greeve et al (21) used a differential mRNA display approach to identify genes that were differentially expressed in selective vulnerable brain regions in AD. In fact, although intracellular neurofibrillary tangles and extracellular and perivascular deposits of β-amyloid, the histopathological hallmarks of AD, are evenly distributed throughout the brain, substantial loss of neurons and synapses occurs only in selective brain regions, such as the hippocampus, the amygdala, the inferior temporal cortex and the enthorhinal cortex (4).…”

Seladin‐1 and testicular germ cell tumours: new insights into cisplatin responsiveness

“…Seladin-1, encoding 3β-hydroxysterol 24-reductase (DHCR24) [19], catalyses the reduction of the 24 double bond in desmosterol to produce cholesterol, which is down-regulated in brain regions affected by Alzheimer's disease [20]. Expression of seladin-1 is widespread in human tissues [20], with the highest levels being observed in the adrenal gland, prostate, lung, and fetal liver.…”

“…Expression of seladin-1 is widespread in human tissues [20], with the highest levels being observed in the adrenal gland, prostate, lung, and fetal liver. In addition, seladin-1 is expressed in the brain and in various endocrine organs, such as adrenal cortex [21][22][23][24], testis, and ovary [20,22,25].…”

“…In addition, seladin-1 is expressed in the brain and in various endocrine organs, such as adrenal cortex [21][22][23][24], testis, and ovary [20,22,25]. Seladin-1 effectively inhibits caspase-3 activity, a key mediator of apoptosis, and protects neuronal cells from apoptotic death [20,26,27], thus suggesting its involvement in the regulation of cell survival and death.…”

“…Seladin-1 is highly expressed in the normal testis, probably due to the presence of steroid-producing cells [20]. However, it is unknown whether seladin-1 plays any role in germ cells or if it is involved in the pathogenesis of germ cell-derived tumours.…”