PTENα regulates endocytosis and modulates olfactory function

Abstract

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) α is the first identified isoform of the well‐known tumor suppressor PTEN. PTENα has an evolutionarily conserved 173‐aa N terminus compared with canonical PTEN. Recently, PTENα has been shown to play roles in multiple biologic processes including learning and memory, cardiac homeostasis, and antiviral immunity. Here, we report that PTENα maintains mitral cells in olfactory bulb (OB), regulates endocytosis in OB neurons, and controls olfactory behaviors in mice. We show that PTENα directly dephosphorylates the endocytic protein amphiphysin and promotes its binding to adaptor‐related protein complex 2 subunit β1 (Ap2b1). In addition, we identified mutations in the N terminus of PTENα in patients with Parkinson disease and Lewy‐body dementia, which are neurodegenerative disorders with early olfactory loss. Overexpression of PTENα mutant H169N in mice OB reduces odor sensitivity. Our data demonstrate a role of PTENα in olfactory function and provide insight into the mechanism of olfactory dysfunction in neurologic disorders.—Yuan, Y., Zhao, X., Wang, P., Mei, F., Zhou, J., Jin, Y., McNutt, M. A., Yin, Y. PTENα regulates endocytosis and modulates olfactory function. FASEB J. 33, 11148–11162 (2019). http://www.fasebj.org

PTENα is responsible for protection of brain against oxidative stress during aging

“…In the hippocampus, PTENα principally modulates CaMKII signaling to regulate learning and memory 32 . In the OB, PTENα mainly modulates the olfactory function by regulating endocytosis 33 . In this study, PTENα is primarily responsible for regulation of the antioxidant pathway in the midbrain.…”

“…Ptenα is predominantly expressed in the brain, especially in the OB, midbrain, cortex, and hippocampus 32 . Our preliminary data has shown Ptenα levels in the OB gradually declined with increasing age after adulthood 33 . Ptenα expression patterns in mouse midbrain, cortex, and hippocampus were further evaluated.…”

“…32 Our preliminary data has shown Ptenα levels in the OB gradually declined with increasing age after adulthood. 33 Ptenα expression patterns in mouse midbrain, cortex, and hippocampus were further evaluated. As age increased, Ptenα levels displayed an obvious reduction (Figure 1E,F).…”

“…3.5 | PTENα p.H169N is predicted to alter protein function Point mutation c.C505A, p.H169N, which was identified in PD patients, is a missense mutation that locates in the specific N-terminus of PTENα. 33 We would like to determine whether this mutation altered the capacity of PTENα to regulate COX4. Exogenous PTENα and PTENα H169N mutants were separately transfected into PTENα −/− Hela cells, and the endogenous expression of COX4 was examined under stress.…”

“…PTENα is the longest isoform of PTEN that translates from a nonclassical start codon CUG and, compared to PTEN, contains an evolutionarily conserved extended 173‐aa N‐terminus 30,31 . Several studies have revealed the extended N‐terminus confers multiple specific functions to PTENα: maintaining mitochondrial energy metabolism through the Parkin‐Pink1 pathway 31 ; regulating fear‐conditioned memory through CaMKIIα signaling 32 ; and participating in olfaction process by modulating endocytosis 33 . Diminished olfaction is a common feature of aging and our preliminary data showed PTENα gradually declines with increasing age in mouse olfactory bulb (OB), 33 raising the possibility that PTENα decline might associate with aging process.…”