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TDAG51 Mediates Negative Signaling Crosstalk Between NGF/p75NTR-Induced Cell Death and GDNF/RET-Promoted Survival in
Fernando Federicci1, Fernanda Ledda2, Gustavo Paratcha3
1Laboratorio de Neurociencia Molecular y Celular, Instituto de Biología Celular y Neurociencias (IBCN)-CONICET-UBA, Facultad de Medicina, Universidad de Buenos Aires (UBA), Buenos Aires, CP1121, Argentina.
Abstract:
GDNF is a potent survival and differentiation factor for motor neurons and other central and peripheral neuronal populations. While the signaling pathways by which GDNF promotes survival/differentiation have been relatively well established, the molecular mechanisms that restrict its biological effects remain unclear. In this study, we show that TDAG51 plays a role in regulating the GDNF-induced PI3K/AKT survival pathway. Our findings demonstrate that treatment of motor neuron-derived MN1 cells with high levels of nerve growth factor (NGF), a treatment that under oxidative conditions promotes p75 neurotrophin receptor (p75NTR)-dependent motor neuron apoptosis, induces TDAG51, which in turn inhibits GDNF/RET-mediated AKT signaling. Moreover, knockdown of Tdag51 potentiates the ability of GDNF to activate AKT and provides protection against NGF-induced p75NTR-dependent cell death in MN1 cells. Mechanistically, short-term GDNF stimulation of MN1 cells expressing high levels of TDAG51 promotes the translocation and recruitment of TDAG51 into detergent-resistant plasma membrane microdomains via a PI3K-dependent mechanism. The NGF/p75NTR signaling-induced increase in TDAG51 levels antagonizes AKT activation triggered by GDNF/RET signaling, likely by interfering with AKT´s interaction with PIP3. Taken together, our results demonstrate that TDAG51 is a key mediator of the balance between NGF-induced p75NTR-promoted apoptotic pathway and GDNF/RET-mediated survival signaling in MN1 neuronal cells.
Insights
TDAG51 regulates motor neuron survival by modulating GDNF/RET and NGF/p75NTR pathways. TDAG51 inhibition enhances GDNF-mediated AKT activation and protects against NGF-induced apoptosis.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Signaling
Background:
- Glial cell line-derived neurotrophic factor (GDNF) is crucial for motor neuron survival and differentiation.
- The precise molecular mechanisms limiting GDNF's biological effects are not fully understood.
- Nerve growth factor (NGF) can induce motor neuron apoptosis via the p75 neurotrophin receptor (p75NTR) under specific conditions.
Purpose of the Study:
- To investigate the role of TDAG51 in regulating GDNF-mediated survival pathways.
- To elucidate how TDAG51 influences the balance between pro-survival (GDNF/RET) and pro-apoptotic (NGF/p75NTR) signaling in motor neurons.
Main Methods:
- Utilized motor neuron-derived MN1 cells.
- Investigated the effects of GDNF and NGF treatments on TDAG51 expression and signaling pathways.
- Employed knockdown of Tdag51 to assess its functional role.
- Analyzed protein translocation and interactions using biochemical methods, including assessment of plasma membrane microdomains.
Main Results:
- High NGF levels induce TDAG51, which inhibits GDNF/RET-mediated AKT signaling in MN1 cells.
- Knockdown of Tdag51 potentiates GDNF-induced AKT activation and confers protection against NGF/p75NTR-dependent cell death.
- TDAG51 translocates to detergent-resistant membrane microdomains upon GDNF stimulation via a PI3K-dependent mechanism.
- TDAG51 antagonizes GDNF/RET-mediated AKT activation, likely by interfering with AKT and PIP3 interaction.
Conclusions:
- TDAG51 acts as a critical regulator of the interplay between NGF-induced apoptosis and GDNF-mediated survival signaling in MN1 neuronal cells.
- TDAG51's inhibitory effect on AKT signaling is a key mechanism by which it modulates neuronal fate decisions.
- Targeting TDAG51 may offer a therapeutic strategy for neurodegenerative conditions affecting motor neurons.
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