| First Author | Teranishi Y | Year | 2015 |
| Journal | FEBS J | Volume | 282 |
| Issue | 17 | Pages | 3438-51 |
| PubMed ID | 26094765 | Mgi Jnum | J:248987 |
| Mgi Id | MGI:6093233 | Doi | 10.1111/febs.13353 |
| Citation | Teranishi Y, et al. (2015) Proton myo-inositol cotransporter is a novel gamma-secretase associated protein that regulates Abeta production without affecting Notch cleavage. FEBS J 282(17):3438-51 |
| abstractText | gamma-Secretase is a transmembrane protease complex that is responsible for the processing of a multitude of type 1 transmembrane proteins, including the amyloid precursor protein and Notch. gamma-Secretase processing of amyloid precursor protein results in the release of the amyloid beta-peptide (Abeta), which is involved in the pathogenesis in Alzheimer's disease. Processing of Notch leads to the release of its intracellular domain, which is important for cell development. gamma-Secretase associated proteins (GSAPs) could be of importance for substrate selection, and we have previously shown that affinity purification of gamma-secretase in combination with mass spectrometry can be used for finding such proteins. In the present study, we used this methodology to screen for novel GSAPs from human brain, and studied their effect on Abeta production in a comprehensive gene knockdown approach. Silencing of probable phospholipid-transporting ATPase IIA, brain-derived neurotrophic factor/neurotrophin-3 growth factor receptor precursor and proton myo-inositol cotransporter (SLC2A13) showed a clear reduction of Abeta and these proteins were selected for further studies on Abeta production and Notch cleavage using small interfering RNA-mediated gene silencing, as well as an overexpression approach. Silencing of these reduced Abeta secretion in a small interfering RNA dose-dependent manner. Interestingly, SLC2A13 had a lower effect on Notch processing. Furthermore, overexpression of SLC2A13 increased Abeta40 generation. Finally, the interaction between gamma-secretase and SLC2A13 was confirmed using immunoprecipitation and a proximity ligation assay. In summary, SLC2A13 was identified as a novel GSAP that regulates Abeta production without affecting Notch cleavage. We suggest that SLC2A13 could be a target for Abeta lowering therapy aimed at treating Alzheimer's disease. |
