Command Palette

Search for a command to run...

Preprint WatchModerateSeptember 5th, 2026

Defective synapto-nuclear signaling contributes to motoneuron vulnerability in SOD1-ALS

Grycz, K.; Jan, C.; Zawistowski, P.; Wasicki, B.; Ozkan, B.; Aousji, O.; Sirtori, R.; Fallini, C.; Caron, G.; Danner, S. M.; Roselli, F.; Zytnicki, D.; Baczyk, M.

Defective synapto-nuclear signalling at glutamatergic excitatory synapses contributes to motoneuron vulnerability in SOD1 amyotrophic lateral sclerosis, placing the pathogenic step in activity-dependent transcriptional coupling.

Moderate contradiction

1 prior failure

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

This preprint reports that defective synapto-nuclear signalling at glutamatergic excitatory synapses contributes to motoneuron vulnerability in SOD1 models of amyotrophic lateral sclerosis, locating the pathogenic step in activity-dependent transcriptional coupling rather than in bulk oxidative damage. The Claidex graph holds one SOD1 associated failure, mt-1186-oral-edaravone-sod1-als-phase3-futility, in which an oral free radical scavenger was stopped for futility in the same disease. The two are not in direct conflict, but they point in different therapeutic directions. The failed programme treated oxidative damage as the proximate driver, while this work places the vulnerability upstream in synaptic signal transduction. The flag is moderate because the single prior record is a Phase 3 efficacy failure, and any programme built on this preprint should state explicitly how its mechanism and its pharmacodynamic readout differ from the scavenger hypothesis that already failed.

Abstract excerpt

Glutamatergic excitatory synapses not only shape spiking activity and neuronal communication but also initiate activity-dependent signaling pathways that trigger transcriptional programs. Since glutamatergic excitatory synapses onto spinal motoneurons (MNs) are impaired presymptomatically in Amyotrophic Lateral Sclerosis, we investigated whether synapto-nuclear coupling is disrupted in MNs from mSOD1 mice and whether restoring it mitigates pathology. We developed an in vivo approach to selectively investigate the coupling between synaptic excitation and nuclear CREB phosphorylation in spinal MNs. Specific activation of Ia-MN synapses induces CREB phosphorylation in wild-type MNs but not in mSOD1 MNs at P50, indicating presymptomatic synapto-nuclear uncoupling. Enhancing cAMP/PKA signaling by pharmacological inhibition of cAMP degradation restored synapto-nuclear coupling, reduced misfolded SOD1, and slowed neuromuscular-junction denervation. Thus, activity-dependent synapto-nuclear signaling is impaired yet pharmacologically rescuable in mSOD1 MNs, supporting synapto-nuclear signaling as a determinant of MN resilience.

Matching Claidex post-mortems

1 of 1 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.