Expression of NALP1 in cerebellar granule neurons stimulates apoptosis.
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.
Liu
Feng
F
Wyeth Neuroscience Discovery Research, CN 8000, Princeton, NJ 08543, USA. liuf@wyeth.com
Lo
C Frederick
CF
Ning
Xiaoping
X
Kajkowski
Eileen M
EM
Jin
Mei
M
Chiriac
Camelia
C
Gonzales
Cathleen
C
Naureckiene
Saule
S
Lock
Yeung-Wai
YW
Pong
Kevin
K
Zaleska
Margaret M
MM
Jacobsen
J Steven
JS
Silverman
Sanford
S
Ozenberger
Bradley A
BA
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
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