Islet-brain1/C-Jun N-terminal kinase interacting protein-1 (IB1/JIP-1) promoter variant is associated with Alzheimer's disease.
Islet-brain1 (IB1) or c-Jun NH2 terminal kinase interacting protein-1 (JIP-1), the product of the MAPK8IP1 gene, functions as a neuronal scaffold protein to allow signalling specificity. IB1/JIP-1 interacts with many cellular components including the reelin receptor ApoER2, the low-density lipoprotein receptor-related protein (LRP), kinesin and the Alzheimer's amyloid precursor protein. Coexpression of IB1/JIP-1 with other components of the c-Jun NH2 terminal-kinase (JNK) pathway activates the JNK activity; conversely, selective disruption of IB1/JIP-1 in mice reduces the stress-induced apoptosis of neuronal cells. We therefore hypothesized that IB1/JIP-1 is a risk factor for Alzheimer's disease (AD). By immunocytochemistry, we first colocalized the presence of IB1/JIP-1 with JNK and phosphorylated tau in neurofibrillary tangles. We next identified a -499A>G polymorphism in the 5' regulatory region of the MAPK8IP1 gene. In two separate French populations the -499A>G polymorphism of MAPK8IP1 was not associated with an increased risk to AD. However, when stratified on the +766C>T polymorphism of exon 3 of the LRP gene, the IB1/JIP-1 polymorphism was strongly associated with AD in subjects bearing the CC genotype in the LRP gene. The functional consequences of the -499A>G polymorphism of MAPK8IP1 was investigated in vitro. In neuronal cells, the G allele increased transcriptional activity and was associated with an enhanced binding activity. Taken together, these data indicate that the increased transcriptional activity in the presence of the G allele of MAPK8IP1 is a risk factor to the onset of in patients bearing the CC genotype of the LRP gene.
Helbecque
N
N
Institut National de la Santé et de la Recherche Médicale U508, Pasteur Institute, Lille, France.
Abderrahamani
A
A
Meylan
L
L
Riederer
B
B
Mooser
V
V
Miklossy
J
J
Delplanque
J
J
Boutin
P
P
Nicod
P
P
Haefliger
J-A
JA
Cottel
D
D
Amouyel
P
P
Froguel
P
P
Waeber
G
G
Abderrhamani
A
A
D048868:Adaptor Proteins, Signal Transducing; D000544:Alzheimer Disease / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D001344:Autopsy; D001483:Base Sequence; D001921:Brain / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics*; D003071:Cognition; D017931:DNA Primers; D005602:France; D014644:Genetic Variation; D006801:Humans; D009447:Neuroblastoma; D009687:Nuclear Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D000091042:Reelin Protein; D015534:Trans-Activators / Q000235:genetics*; D014162:Transfection; D014407:Tumor Cells, Cultured
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D017931:DNA Primers; C490666:MAPK8IP1 protein, human; D009687:Nuclear Proteins; D000091042:Reelin Protein; D015534:Trans-Activators; C000717127:RELN protein, human; C000717128:Reln protein, mouse