title: Negative regulation of Grb10 Interacting GYF Protein 2 on insulin-like growth factor-1 receptor signaling pathway caused diabetic mice cognitive impairment.
abstract: Heterozygous Gigyf2⁺/⁻ mice exhibits histopathological evidence of neurodegeneration such as motor dysfunction. Several lines of evidence have demonstrated the important role of insulin-like growth factor-1 receptor (IGF1R) signaling pathway in the neuropathogenic process of cognitive impairment, while decreased Grb10-Interacting GYF Protein 2 (GIGYF2) expression can alter IGF1R trafficking and its downstream signaling pathways. Growth factor receptor-bound protein 10 (Grb10), a suppressor of IGF1R pathway, has been shown to play a critical role in regulating diabetes-associated cognitive impairment. It remains unknown whether endogenous GIGYF2 expression contributes to the development of diabetes-associated cognitive impairment. Using streptozotocin (STZ)-induced diabetic mice model, we first demonstrated that a significantly increased level of GIGYF2 expression was correlated with a significant decrease in the expression of phosphorylated IGF1R as well as the phosphorylation of AKT and ERK1/2, two signaling pathways downstream of IGF1R, in the hippocampus of diabetic mice. On the contrary, in situ knockdown of GIGYF2 expression in hippocampus resulted in increased expression of phosphorylated IGF1R expression and correspondingly reversed the down-regulation of ERK1/2 phsophorylation but had no obvious effect on Grb10 expression. Functionally, knockdown of GIGYF2 expression markedly ameliorated diabetes-associated cognitive dysfunction as well as the ultrastructural pathology and abnormal neurobehavioral changes. These results suggest that increased expression of GIGYF2 might contribute to the development of diabetes-associated cognitive disorder via negatively regulating IGF1R signaling pathway. Therefore, down-regulation of GIGYF2 expression may provide a potential novel approach to treat diabetes-associated cognitive impairment caused by aberrant IGF1R signaling pathway.
authors.affiliation: Department of Geriatrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Xie
authors.affiliation: Department of Geriatrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Qianping
authors.initials: Q
authors.lastname: Wei
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Huacong
authors.initials: H
authors.lastname: Deng
authors.affiliation: Department of Mental Health, The Mental Health Center of Jiulongpo District, Chongqing, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Geriatrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Lingli
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Geriatrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zeng
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D003071:Cognition; D003072:Cognition Disorders / Q000150:complications / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D051383:GRB10 Adaptor Protein / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D015316:Genetic Therapy; D006624:Hippocampus / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D017451:Receptors, Somatomedin / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013311:Streptozocin
chemical_list: D002352:Carrier Proteins; C547020:GIGYF2 protein, mouse; C495959:Grb10 protein, mouse; D034741:RNA, Small Interfering; D017451:Receptors, Somatomedin; D051383:GRB10 Adaptor Protein; D013311:Streptozocin; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3