title: Alteration of caspases and other apoptosis regulatory proteins in Down syndrome.
abstract: Apoptosis has been implicated in the selective neuronal loss of Down syndrome (DS). Apoptosis activates a family of cysteine proteases with specificity for aspartic acid residues referred to as caspases that play a key role in dismantling a cell committed to die. Caspase activity is regulated by a variety of proteins that possess a domain resembling the prodomains of caspases. Little is known, however, about the changes of caspases and their regulatory proteins in DS. Here, we investigated levels of nine such different proteins by western blot technique in frontal cortex and cerebellum of control and DS subjects. The protein levels of DFF45 (DNA fragmentation factor 45), and FLIP (FADD like interleukin-1beta-converting enzyme inhibitory proteins) were significantly decreased whereas that of RICK (RIP-like interacting CLARP kinase) increased in both regions of DS. In contrast, cytochrome c, Apaf-1 (apoptosis protease activating factor-1), procaspase-9 and ARC (apoptosis repressor with caspase recruitment domain) were unchanged. Procaspase-3 and -8 were significantly decreased in frontal cortex but no significant change was observed in cerebellum. Regression analysis revealed no correlation between postmortem interval and levels of the investigated proteins. However, inconsistent correlation was found between age and levels of proteins as well as amongst the density of individual proteins. These findings demonstrate that dysregulation of apoptotic proteins does exist in DS brain and may underlie the neuropathology of DS. The study further suggests that apoptosis in DS may occur via the death receptor pathway independent of cytochrome c. Hence, therapeutic strategies that target caspase activation may prove useful in combating neuronal loss in this disorder.
authors.affiliation: Department of Pediatrics, University of Vienna, Austria.
authors.forename: T
authors.initials: T
authors.lastname: Gulesserian
authors.forename: E
authors.initials: E
authors.lastname: Engidawork
authors.forename: B C
authors.initials: BC
authors.lastname: Yoo
authors.forename: N
authors.initials: N
authors.lastname: Cairns
authors.forename: G
authors.initials: G
authors.lastname: Lubec
mesh_terms: D000368:Aged; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D053477:Apoptotic Protease-Activating Factor 1; D015153:Blotting, Western; D001921:Brain / Q000201:enzymology / Q000473:pathology; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins / Q000378:metabolism; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D003574:Cytochrome c Group / Q000378:metabolism; D004314:Down Syndrome / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2
chemical_list: C506592:APAF1 protein, human; D051017:Apoptosis Regulatory Proteins; D053477:Apoptotic Protease-Activating Factor 1; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D002352:Carrier Proteins; D003574:Cytochrome c Group; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; C112246:NOL3 protein, human; D011506:Proteins; C109664:caspase-activated DNase inhibitor; D011494:Protein Kinases; C506253:RIPK2 protein, human; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases