The acquired toxicity of the familial amyotrophic lateral sclerosis (ALS)-associated mutant Zn-superoxide dismutase 1 (SOD1) protein has been implicated in motoneuron death, and cytosolic aggregates or inclusions have been observed in the cytoplasm of motoneurons, astrocytes, and neuronal axons but not in that of microglia. This study elucidates the mechanisms by which mutant SOD1 does not aggregate in and is cleared by microglia. We generated pcDNA3-Venus-tagged SOD1 constructs: wild-type SOD1 and mutant SOD1 were used as controls, and the A4V, D90A, and G93A SOD1 mutants were used as disease-related constructs; these plasmids were introduced into the Ra2 microglia line for subsequent evaluation. In spinal cords collected from postsymptomatic G93A mice, very little aggregation of the mutant SOD1 protein was detected in microglia, consistent with previous reports. Our new findings, which were based on immunohistochemical, Western blot, and enzyme immunoassay analyses, revealed that the protein expression of mutant SOD1 in microglia is significantly lower than that of wild-type SOD1. Furthermore, we observed the recovery of mutant SOD1 protein levels in autophagy suppression experiments and its colocalization with WDFY3, a selective autophagy-related protein. These in vitro results demonstrate that only the mutant SOD1 protein (i.e., not wild-type SOD1) is degraded by selective autophagy. Furthermore, we found that both wild-type and mutant SOD1 are secreted directly from microglia. These findings provide an opportunity to elucidate the precise mechanism through which microglia manage mutant SOD1 proteins during the pathological process of ALS and are likely to lead to improvements in ALS treatment strategies.
The trade-off between proactive and reactive cognitive control refers to the dynamic regulation process by which individuals flexibly allocate cognitive resources according to task demands-representing a core feature of cognitive control flexibility. Previous research has shown that emotion can significantly affect this trade-off, but most studies have focused on emotional valence and arousal, lacking a systematic investigation into how emotional motivation influences the trade-off in cognitive control. Using the AX-Continuous Performance Task paradigm, the present study systematically examined the mechanisms by which different emotional motivations impact the trade-off between proactive and reactive control. Results showed that proactive control increased under both approach and avoidance motivation, as indicated by higher Proactive Control Index scores and larger CNV amplitudes than baseline. In contrast, reactive control improved only under avoidance motivation: behaviorally, avoidance enhanced BX performance, and electrophysiologically it produced a larger P3a amplitude than both approach and baseline. Approach motivation did not produce a reliable change in reactive control. These findings suggest that approach and avoidance motivation differentially modulate proactive and reactive control, thereby influencing the dynamic trade-off between cognitive control modes and revealing a regulatory process through which emotion may shape cognitive control strategy selection.

