Exploring the relationship between PTEN and Klotho in autophagy

• Grant number: 25/07676-7
• Support Opportunities: Scholarships abroad - Research Internship - Master's degree
• Start date: January 05, 2026
• End date: June 04, 2026
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal Investigator: Elisa Mitiko Kawamoto Iwashe
• Grantee: Geovana Rosa Oliveira dos Santos
• Supervisor: Daniel Charles Berwick
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: City St George'S, University Of London, England
• Associated to the scholarship: 24/07231-2 - Evaluation of the expression of glutamatergic receptors in the cerebellum in a cellular model of Klotho deletion: possible modulatory role of beta-estradiol, BP.MS

Abstract

PTEN is a tumor suppressor that plays an important role in cellular survival, growth and proliferation. In the brain, PTEN has been shown to regulate neurogenesis, synaptic plasticity, and learning. Therefore, PTEN deletion has been associated with some neurological disorders. Besides that, PTEN inhibits the PI3K-Akt-mTOR pathway, a highly conserved pathway that negatively regulates autophagy. Autophagy is the homeostatic process that degrades and recycles proteins and cellular organelles and regulates neuronal development and synaptic plasticity, which is dependent on the N-methyl-D-aspartate (NMDA) receptor and involves ¿-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor degradation. The autophagic process also involves Rab proteins, such as Rab7 and Rab11, which regulate the degradative and secretory autophagy machinery,respectively. In turn, Klotho is a protein associated with longevity and has been shown to downregulate the PI3K/Akt-mTOR pathway. Previous studies of our group show that Klotho reverses the effects of siRNA-mediated PTEN silencing in HEK293T cells on Rab7 diffusion, suggesting that Klotho could be used as a treatment to revert the neuronal morphological alterations caused by PTEN deletion. The main objective of this project research is investigating the relationship between PTEN and Klotho in autophagy-related markers such as LC3 protein, PI3K-Akt-mTOR pathway components, and Rab7 and Rab11 proteins, in CRISPr-Cas9-mediated PTEN-knockout cells, in the presence or absence of Klotho overexpressing plasmids. These results could elucidate the PTEN-Klotho interaction in the autophagic process.