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Preprint WatchModerateJune 12th, 2026

Mutant SOD1 expressed by oligodendrocytes aggregates in myelinic nanochannels and accelerates disease progression in familial ALS mice

Mot, A. I.; Li, Y.; Dibaj, P.; Tzvetanova, I. D.; Gerwig, U. C.; Bogale, T. A.; Goebbels, S.; Möbius, W.; Bergles, D. E.; Morrison, B. M.; Rothstein, J. D.; Cleveland, D. W.; Edgar, J. M.; Nave, K.-A.

Mutant SOD1 expressed in oligodendrocytes aggregates in myelinic nanochannels and accelerates disease progression, while excision of mutant SOD1 in the oligodendrocyte lineage before myelin compaction slows onset and prolongs survival in familial ALS mice.

Moderate contradiction

1 prior failure

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

This preprint strengthens SOD1 as a causal, timing-sensitive driver in familial ALS by showing that oligodendrocyte-intrinsic mutant SOD1 aggregation accelerates disease, while early excision of the mutant gene slows onset and extends survival. The indexed Claidex post-mortem mt-1186-oral-edaravone-sod1-als-phase3-futility recorded a Phase 3 efficacy failure of oral edaravone, an antioxidant that does not lower or clear mutant SOD1. The new data do not contradict that failure. They point away from downstream oxidative-stress modulation and toward cell-type-specific SOD1 lowering delivered before myelin compaction, which is consistent with the efficacy gap seen when the mutant protein itself is left in place.

Abstract excerpt

Amyotrophic lateral sclerosis (ALS) is a highly debilitating and fatal disease characterized by the progressive loss of motor neurons. Reduced oligodendroglial support has been implicated in ALS progression but remains mechanistically unexplained. Here, using a mutant superoxide dismutase 1 (SOD1-G37R) mouse model of familial ALS, Cre-mediated excision of the mutant SOD1 gene within the oligodendrocyte lineage prior to myelin compaction is shown to slow disease onset, improve motor performance, and prolong survival. In contrast, silencing mutant SOD1 expression within oligodendrocytes after myelin compaction failed to ameliorate disease phenotype. Electron microscopy is used to identify aggregation of mutant SOD1 within paranodal loops and the inner periaxonal tongue of myelinic nanochannels, narrow cytosolic compartments for the diffusion of metabolites and motor-driven transport processes. In a second mouse model (SOD1-G93A) of familial, SOD1 mutant-mediated ALS, we show that induction of excessive myelin compaction and myelinic channel collapse (by depletion of CNP from myelin) accelerates disease and diminishes survival. Our data support loss of myelinic channel integrity as a contributor to familial ALS disease initiation and progression, findings likely relevant to neurodegenerative disease involving other aggregation prone proteins that are expressed in myelinating oligodendrocytes.

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.