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

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 lowdensity 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 À499A4G polymorphism in the 5' regulatory region of the MAPK8IP1 gene. In two separate French populations the À499A4G polymorphism of MAPK8IP1 was not associated with an increased risk to AD. However, when stratified on the þ 766C4T 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 -499A4G 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.

Phosphorylated Tau Interacts with c-Jun N-terminal Kinase-interacting Protein 1 (JIP1) in Alzheimer Disease

“…Our in vivo finding that JIP1 fails to interact with KLC and is instead bound by phosphorylated Tau and retained in the cell body is consistent with an increased JIP1 staining in the soma of neurons in both K3 mice and in AD (49). Because JIP1 is also a scaffolding protein for several kinases, many of which phosphorylate Tau, it cannot be excluded that JIP1 mislocalization may also promote hyperphosphorylation of Tau in the soma, establishing a vicious cycle.…”

Phosphorylation of neurofilament subunit NF‐M is regulated by activation of NMDA receptors and modulates cytoskeleton stability and neuronal shape

“…Immunofluorescent staining was performed as previously described [Bondallaz et al, 2006;Cueille et al, 2007] and images were acquired using a confocal microscope (Leica TCS NT) according to Helbecque et al [2003].…”

Apolipoprotein E, cholesterol metabolism, diabetes, and the convergence of risk factors for Alzheimer's disease and cardiovascular disease

“…This polymorphism was not found to be linked to AD in the general population, however a strong association was found in subjects also carrying a particular LRP gene polymorphism (CC genotype). 163 A separate polymorphism in the MAPK81P1 gene has been linked with diabetes. 164 A missense mutation in the coding region of this gene segregated with diabetes in a diabetes type II family.…”

“…162 Recent studies have linked a polymorphism in the MAPK81P1 gene with AD. 163 This gene codes for islet-brain1 (IB1, DNA-binding transactivator of the glucose transporter GLUT2)/c-Jun N-terminal kinase interacting protein-1 (JIP-1), a neuronal scaffold protein that interacts with several membrane proteins including LRP, ApoE e2, the reelin receptor, and APP. The À499A > G promoter polymorphism in MAPK81P1 causes an increase in transcription, resulting in enhanced binding activity.…”