PHLDA restricts the anti-apoptotic effects of GDNF by inhibiting Ret-mediated Akt signaling pathway

FEDERICCI, FERNANDO; LEDDA, FERNANDA; PARATCHA, GUSTAVO

Buenos Aires

Congreso; Reunion anual de la Sociedad Argentina de Investigacion en Neurociencias; 2022

Sociedad Argentina de Investigacion en Neurociencias

GDNF is a potent survival factor for different neuronal populations in the peripheral andcentral nervous system, including spinal cord motor neurons. While the signalingpathways by which GDNF promotes survival are relatively well established, themolecular mechanisms that restrict the anti-apoptotic effect of this neurotrophic factorremain unknown. In the current study, we show that in the motor neuron-derived cellline 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 promotesthe localization and recruitment of PHLDA (a protein mainly cytoplasmic) towards theplasma membrane, indicating that PHLDA could regulate proximal downstreamsignaling events triggered by GDNF and its tyrosine kinase receptor Ret. In line withthis finding, we show that PHLDA has the ability to inhibit Akt, but not MAPK activationin response to GDNF. Finally, the overexpression of PHLDA restricts theneuroprotective effect of GDNF on cellular apoptosis induced by serum deprivation.Together, these results provide an insight into PHLDA function and establish a newmolecular mechanism to restrict signaling and biological responses induced by GDNFand its receptor Ret in neuronal cells.