title: The novel presenilin-1-associated protein is a proapoptotic mitochondrial protein.
abstract: Recent studies have suggested a possible role for presenilin proteins in apoptotic cell death observed in Alzheimer's disease. The mechanism by which presenilin proteins regulate apoptotic cell death is not well understood. Using the yeast two-hybrid system, we previously isolated a novel protein, presenilin-associated protein (PSAP) that specifically interacts with the C terminus of presenilin 1 (PS1), but not presenilin 2 (PS2). Here we report that PSAP is a mitochondrial resident protein sharing homology with mitochondrial carrier protein. PSAP was detected in a mitochondria-enriched fraction, and PSAP immunofluorescence was present in a punctate pattern that colocalized with a mitochondrial marker. More interestingly, overexpression of PSAP caused apoptotic death. PSAP-induced apoptosis was documented using multiple independent approaches, including membrane blebbing, chromosome condensation and fragmentation, DNA laddering, cleavage of the death substrate poly(ADP-ribose) polymerase, and flow cytometry. PSAP-induced cell death was accompanied by cytochrome c release from mitochondria and caspase-3 activation. Moreover, the general caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone, which blocked cell death, did not block the release of cytochrome c from mitochondria caused by overexpression of PSAP, indicating that PSAP-induced cytochrome c release was independent of caspase activity. The mitochondrial localization and proapoptotic activity of PSAP suggest that it is an important regulator of apoptosis.
authors.affiliation: Department of Pathology, College of Veterinary Medicine, University of Tennessee, Knoxville 37996, USA.
authors.forename: Xuemin
authors.initials: X
authors.lastname: Xu
authors.forename: Yong-chang
authors.initials: YC
authors.lastname: Shi
authors.forename: Wei
authors.initials: W
authors.lastname: Gao
authors.forename: Guozhang
authors.initials: G
authors.lastname: Mao
authors.forename: Guojun
authors.initials: G
authors.lastname: Zhao
authors.forename: Sudesh
authors.initials: S
authors.lastname: Agrawal
authors.forename: Guy M
authors.initials: GM
authors.lastname: Chisolm
authors.forename: Dexin
authors.initials: D
authors.lastname: Sui
authors.forename: Mei-Zhen
authors.initials: MZ
authors.lastname: Cui
mesh_terms: D000595:Amino Acid Sequence; D017209:Apoptosis / Q000502:physiology*; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D003574:Cytochrome c Group / Q000378:metabolism; D017931:DNA Primers; D004789:Enzyme Activation; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008969:Molecular Sequence Data; D053764:Presenilin-1; D017386:Sequence Homology, Amino Acid
chemical_list: D003574:Cytochrome c Group; D017931:DNA Primers; C402222:MTCH1 protein, human; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D020169:Caspases