alpha-synuclein and Hyperplasia

Type 2 diabetes is characterised by hyperglucagonaemia and perturbed function of pancreatic glucagon-secreting alpha cells but the molecular mechanisms contributing to these phenotypes are poorly understood. Insulin-degrading enzyme (IDE) is present within all islet cells, mostly in alpha cells, in both mice and humans. Furthermore, IDE can degrade glucagon as well as insulin, suggesting that IDE may play an important role in alpha cell function in vivo.. We have generated and characterised a novel mouse model with alpha cell-specific deletion of Ide, the A-IDE-KO mouse line. Glucose metabolism and glucagon secretion in vivo was characterised; isolated islets were tested for glucagon and insulin secretion; alpha cell mass, alpha cell proliferation and α-synuclein levels were determined in pancreas sections by immunostaining.. Targeted deletion of Ide exclusively in alpha cells triggers hyperglucagonaemia and alpha cell hyperplasia, resulting in elevated constitutive glucagon secretion. The hyperglucagonaemia is attributable in part to dysregulation of glucagon secretion, specifically an impaired ability of IDE-deficient alpha cells to suppress glucagon release in the presence of high glucose or insulin. IDE deficiency also leads to α-synuclein aggregation in alpha cells, which may contribute to impaired glucagon secretion via cytoskeletal dysfunction. We showed further that IDE deficiency triggers impairments in cilia formation, inducing alpha cell hyperplasia and possibly also contributing to dysregulated glucagon secretion and hyperglucagonaemia.. We propose that loss of IDE function in alpha cells contributes to hyperglucagonaemia in type 2 diabetes.

Topics: alpha-Synuclein; Animals; Cell Proliferation; Diabetes Mellitus, Type 2; Glucagon; Glucagon-Secreting Cells; Hyperplasia; Insulin; Insulin-Secreting Cells; Insulysin; Mice

The synucleins (alpha, beta, and gamma) are a family of small cytoplasmic proteins that are expressed predominantly in neurons. alpha synuclein has attracted considerable attention due to its involvement in neurodegenerative diseases. Abnormal expression of gamma synuclein has recently been reported in some breast tumors. In this study, the authors examined a panel of breast and ovarian carcinomas for expression of alpha, beta, and gamma synucleins.. Normal breast and ovary tissue samples, tissue from ovaries of women at high risk of ovarian carcinoma, and tissue from breast and ovarian carcinomas were screened by immunohistochemistry and Western blot analysis for synuclein expression.. Synucleins were not detectable by Western blot analysis in normal breast tissue. Eighty-two percent (14 of 17) of Stage III/IV breast ductal carcinomas expressed beta synuclein, gamma synuclein, or both simultaneously. Expression of alpha synuclein was not detected in breast carcinomas by Western blot analysis. Synuclein (alpha, beta, and gamma) expression was not detectable by immunohistochemistry in normal ovarian epithelium. Eighty-seven percent (39 of 45) of ovarian carcinomas were found to express at least 1 type of synuclein, and 42% (19 of 45) expressed all 3 synucleins (alpha, beta, and gamma) simultaneously. Highly punctate gamma synuclein expression was also observed in 20% of preneoplastic lesions of the ovary, including epithelial inclusion cysts, hyperplastic epithelium, and papillary structures, suggesting that gamma synuclein up-regulation may occur early in the development of some ovarian tumors.. alpha, beta, and gamma synuclein are expressed in a high percentage of ovarian and breast carcinomas, and abnormal gamma synuclein expression may occur early in the development of ovarian carcinoma.

Topics: Adenocarcinoma; alpha-Synuclein; beta-Synuclein; Blotting, Western; Breast; Breast Neoplasms; Carcinoma; Carcinoma, Ductal, Breast; Cystadenocarcinoma, Papillary; Epithelial Cells; Female; gamma-Synuclein; Gene Expression Regulation, Neoplastic; Humans; Hyperplasia; Immunohistochemistry; Nerve Tissue Proteins; Ovarian Cysts; Ovarian Neoplasms; Ovary; Phosphoproteins; Polymerase Chain Reaction; Precancerous Conditions; Synucleins; Tumor Cells, Cultured