title: Impaired insulin signaling in an animal model of Niemann-Pick Type C disease.
abstract: Studies have shown similarities between the histopathological characteristics of NPC and Alzheimer's disease (AD) including amyloid and tau pathologies. While dysfunction in insulin signaling was widely detected in AD brain, the function of insulin signaling proteins has not been examined in NPC disease. In this study, we have examined the expression and phosphorylation of proteins linked to the insulin signaling pathway in the brain of 9 weeks old NPC(nih) mice. Our results showed lower expression of insulin receptor substrate 2 (IRS2) in the NPC(nih) mice, and insulin receptor substrate 1 (IRS1) expression was almost non-detectable in this NPC mouse model. This reduction was associated with the loss of expression for the regulatory p85 subunit of phosphatidylinositol 3-kinase (p85/PI3K). Interestingly, the impairment was observed to link to a greater reduction of Akt phosphorylation at residue T308 than S473. This aberrant Akt phosphorylation could be contributing to lower GSK3β phosphorylation detected in the NPC(nih) mouse brain. To our knowledge, this is the first report documenting impaired insulin signaling in the brain of a NPC mouse model.
authors: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors: Qi-Rui
authors: QR
authors: Ong
authors: Mei-Li
authors: ML
authors: Lim
authors: Ching-Ching
authors: CC
authors: Chua
authors: Nam Sang
authors: NS
authors: Cheung
authors: Boon-Seng
authors: BS
authors: Wong
mesh_terms: D000818:Animals; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000378:metabolism; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D052556:Niemann-Pick Disease, Type C / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction
chemical_list: D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; C526298:Irs2 protein, mouse; D058543:Class Ia Phosphatidylinositol 3-Kinase; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3