TDAG51 at the crosstalk between GDNF and NGF signal in motor neuron

FEDERICCI, FERNANDO; LEDDA, FERNANDA; PARATCHA, GUSTAVO

Montevideo

Simposio; ALS Beyond the Motor Neuron; 2023

Glial Derived Neurotrophic Factor (GDNF) is a potent survival factor for different neuronal populations in the peripheral and central nervous system, including spinal cord motor neurons. It is well known that GDNF enhance the regeneration and prevent the degeneration of motor neurons, however while the signaling pathways by which GDNF promotes survival are relatively well established, the molecular mechanisms that regulates the effects of this neurotrophic factor remain unknown.Here we show that TDAG51, a molecule first described to be related to pro-apoptotic process, is a novel inhibitor of the signaling and biological effects induced by GDNF and its receptor Ret in neuronal cells. TDAG51 acts as an mediator of the balance between death signals trigger by the receptor p75NTR and pro-survival effects of the activation of GDNF-Ret in the motor neuron-derived cell line MN1 The balance between prosurvival and proapoptotic signaling determine the fate of the cell. In motor neurons the activation of p75NTR by NGF triggers the pathway leading to the cleavage of Caspase 3 and consequently the initiation of the process of cell death by apoptosis.On the other hand, is well known that GDNF can protect the motor neuron from cell death by activating PI3K. This activation results in an increase in PIP3 levels within an specific region of the cell membrane as are the lipid rafts. Through its PH domain, AKT interact with PIP3 and is translocated to the membrane, where is activated. This activation of AKT leads to the protection of the cell against apoptosis.In this study, we propose that TDAG51 regulates the balance between proapoptotic signals triggered by NGF-p75NTR and the antiapoptotic effects of GDNF-Ret.NGF increase the levels of protein TDAG51 in the cell. In this context when GDNF generates an increase in PIP3, because of having a PH domain, TDAG51 compete with AKT for this substratum. This competition could tilt the balance in favor of proapoptotic signals, thereby promoting cell death in motor neurons.