title: Expression of NALP1 in cerebellar granule neurons stimulates apoptosis.
abstract: NAcht Leucine-rich-repeat Protein 1 (NALP1) contains a putative nucleotide binding site, a region of leucine-rich repeats, and death domain folds at both termini providing protein/protein association functions such as caspase recruitment. We report here that NALP1 gene expression was induced in primary cerebellar granule neurons (CGN) upon injury. Up-regulation of NALP1 was also observed in a model of transient focal ischemia induced by middle cerebral artery occlusion. We investigated the biological consequence of over-expression of NALP1 in both HeLa cells and in CGN. Expression of recombinant NALP1 stimulated cell death in both HeLa cells and CGN by an apoptotic mechanism, demonstrated by the induction of apoptotic nuclear morphology and activation of the apoptotic enzyme caspase-3. Also described here are studies on the mechanism of action studies including deletion analyses and investigations of nucleotide binding, which begin to elucidate a regulatory function for NALP1 in neuronal apoptosis.
authors.affiliation: Wyeth Neuroscience Discovery Research, CN 8000, Princeton, NJ 08543, USA. liuf@wyeth.com
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
authors.forename: C Frederick
authors.initials: CF
authors.lastname: Lo
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Ning
authors.forename: Eileen M
authors.initials: EM
authors.lastname: Kajkowski
authors.forename: Mei
authors.initials: M
authors.lastname: Jin
authors.forename: Camelia
authors.initials: C
authors.lastname: Chiriac
authors.forename: Cathleen
authors.initials: C
authors.lastname: Gonzales
authors.forename: Saule
authors.initials: S
authors.lastname: Naureckiene
authors.forename: Yeung-Wai
authors.initials: YW
authors.lastname: Lock
authors.forename: Kevin
authors.initials: K
authors.lastname: Pong
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Zaleska
authors.forename: J Steven
authors.initials: JS
authors.lastname: Jacobsen
authors.forename: Sanford
authors.initials: S
authors.lastname: Silverman
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Ozenberger
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D001665:Binding Sites; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology*; D003838:Deoxyadenine Nucleotides / Q000378:metabolism / Q000494:pharmacology; D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D016296:Mutagenesis; D000070576:NLR Proteins; D009474:Neurons / Q000378:metabolism* / Q000473:pathology*; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D014162:Transfection
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D003838:Deoxyadenine Nucleotides; D000070576:NLR Proteins; C427903:NLRP1 protein, human; D012333:RNA, Messenger; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; C026600:2'-deoxyadenosine triphosphate