Unique properties of PTEN-L contribute to neuroprotection in response to ischemic-like stress

• Published in: Scientific reports 2019-02, Vol.9 (1), p.3183-3183, Article 3183
• Main Authors: Jochner, Magdalena C. E., An, Junfeng, Lättig-Tünnemann, Gisela, Kirchner, Marieluise, Dagane, Alina, Dittmar, Gunnar, Dirnagl, Ulrich, Eickholt, Britta J., Harms, Christoph
• Format: Article
• Language: English
• Subjects: 14; 14/35; 42; 42/35; 45; 631/45/475/2290; 631/80/2373; 631/80/304; 631/80/86/2366; 64/60; 692/617/375/534; 82; 82/51; 82/58; 96; 96/106; 96/63; Ablation; Apoptosis; Brain research; Cell cycle; Cytosol; Glucose; Grb2 protein; Humanities and Social Sciences; Ischemia; Isoforms; Localization; Lysates; Molecular weight; multidisciplinary; Neurons; Neuroprotection; Oxygen; Peptides; Phosphatase; Proteins; Proteomics; PTEN protein; Science; Science (multidisciplinary); Tensin
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-39438-1

Phosphatase and tensin homolog (PTEN) signalling might influence neuronal survival after brain ischemia. However, the influence of the less studied longer variant termed PTEN-L (or PTENα) has not been studied to date. Therefore, we examined the translational variant PTEN-L in the context of neuronal survival. We identified PTEN-L by proteomics in murine neuronal cultures and brain lysates and established a novel model to analyse PTEN or PTEN-L variants independently in vitro while avoiding overexpression. We found that PTEN-L, unlike PTEN, localises predominantly in the cytosol and translocates to the nucleus 10–20 minutes after glutamate stress. Genomic ablation of PTEN and PTEN-L increased neuronal susceptibility to oxygen-glucose deprivation. This effect was rescued by expression of either PTEN-L indicating that both PTEN isoforms might contribute to a neuroprotective response. However, in direct comparison, PTEN-L replaced neurons were protected against ischemic-like stress compared to neurons expressing PTEN. Neurons expressing strictly nuclear PTEN-L NLS showed increased vulnerability, indicating that nuclear PTEN-L alone is not sufficient in protecting against stress. We identified mutually exclusive binding partners of PTEN-L or PTEN in cytosolic or nuclear fractions, which were regulated after ischemic-like stress. GRB2-associated-binding protein 2, which is known to interact with phosphoinositol-3-kinase, was enriched specifically with PTEN-L in the cytosol in proximity to the plasma membrane and their interaction was lost after glutamate exposure. The present study revealed that PTEN and PTEN-L have distinct functions in response to stress and might be involved in different mechanisms of neuroprotection.