Islet-brain1/C-Jun N-terminal kinase interacting protein-1 (IB1/JIP-1) promoter variant is associated with Alzheimer's disease

Mol Psychiatry. 2003 Apr;8(4):413-22, 363. doi: 10.1038/sj.mp.4001344.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Alzheimer Disease / enzymology
  • Alzheimer Disease / genetics*
  • Alzheimer Disease / pathology
  • Autopsy
  • Base Sequence
  • Brain / pathology
  • Carrier Proteins / genetics*
  • Cognition
  • DNA Primers
  • France
  • Genetic Variation
  • Humans
  • Neuroblastoma
  • Nuclear Proteins / genetics*
  • Promoter Regions, Genetic*
  • Trans-Activators / genetics*
  • Transfection
  • Tumor Cells, Cultured

Substances

  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • DNA Primers
  • MAPK8IP1 protein, human
  • Nuclear Proteins
  • Trans-Activators