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Repaglinide Induces ATF6 Processing and Neuroprotection in Transgenic SOD1G93A Mice
Rafael Gonzalo-Gobernado1,2, Laura Moreno-Martínez2,3,4,5, Paz González1,2
1National Centre for Biotechnology (CNB), Consejo Superior de Investigaciones Científicas (CSIC), 28049 Madrid, Spain.
Modulating the Downstream Regulatory Element Antagonist Modulator (DREAM) and activating transcription factor 6 (ATF6) interaction with repaglinide shows promise for treating Amyotrophic Lateral Sclerosis (ALS). This approach reduced motor neuron loss and improved motor function in mouse models.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- The unfolded protein response (UPR) involves activating transcription factor 6 (ATF6) and Downstream Regulatory Element Antagonist Modulator (DREAM).
- Their interaction is a potential therapeutic target for neurodegenerative diseases.
- Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder characterized by motoneuron loss.
Purpose of the Study:
- To investigate the therapeutic potential of targeting the DREAM-ATF6 interaction in ALS.
- To assess the role of DREAM protein expression in ALS pathogenesis.
Main Methods:
- Utilized SOD1G93A mouse model of ALS.
- Administered repaglinide (RP) to modulate the DREAM-ATF6 interaction.
- Assessed motor function, protein expression (DREAM, ATF6 processing, Collagen XIXα1), motoneuron survival, and glial activation in spinal cord tissue.
Main Results:
- DREAM protein expression was reduced in the spinal cords of SOD1G93A mice.
- RP treatment improved motor strength and reduced Collagen XIXα1 mRNA expression in SOD1G93A mice.
- RP treatment decreased motoneuron loss and glial activation, while increasing ATF6 processing in the spinal cords of treated mice.
Conclusions:
- Modulation of the DREAM-ATF6 interaction via repaglinide ameliorates ALS symptoms in a mouse model.
- DREAM represents a potential therapeutic target for ALS intervention.
- Targeting the UPR pathway offers a promising strategy for ALS treatment.
