Cellular and Molecular Neurobiology
Author: Fernando Federicci | email: fer.federicci@gmail.com
Fernando Federicci 1°, Fernanda Ledda 2°, Gustavo Paratcha 1°
1° Instituto de Biología Celular y Neurociencias (IBCN)-CONICET-UBA.
2° Fundación Instituto Leloir, Instituto de Investigaciones Bioquímicas de Buenos Aires.
GDNF is a potent survival factor for different neuronal populations in the peripheral and central nervous system, including spinal cord motor neurons. While the signaling pathways by which GDNF promotes survival are relatively well established, the molecular mechanisms that restrict the anti-apoptotic effect of this neurotrophic factor remain unknown. In the current study, we show that in the motor neuron-derived cell line MN1, GDNF induces a significant increase in the protein levels of PHLDA (Pleckstrin Homology-Like Domain family A), a molecule originally described as pro-apoptotic. Short-term GDNF stimulation of MN1 cells overexpressing PHLDA promotes the localization and recruitment of PHLDA (a protein mainly cytoplasmic) towards the plasma membrane, indicating that PHLDA could regulate proximal downstream signaling events triggered by GDNF and its tyrosine kinase receptor Ret. In line with this finding, we show that PHLDA has the ability to inhibit Akt, but not MAPK activation in response to GDNF. Finally, the overexpression of PHLDA restricts the neuroprotective effect of GDNF on cellular apoptosis induced by serum deprivation. Together, these results provide an insight into PHLDA function and establish a new molecular mechanism to restrict signaling and biological responses induced by GDNF and its receptor Ret in neuronal cells.