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Edaravone counteracts redox and metabolic disruptions in an emerging zebrafish model of sporadic ALS

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the progressive death of motor neurons.  Most ALS cases are sporadic (sALS), however, animal models of sALS cases are scarce. Here we characterise the face and predictive validity of sALS models. We went beyond motor activity and motor axon morphology, to include circadian, redox, proteostasis, and metabolomic phenotypes. We show that the BPA-induced model shows predictive validity using the approved ALS drug edaravone, and that it is a promising model of ALS-related redox and ER imbalances, contributing to fulfil an unmet need for validated sporadic ALS models (Oliveira et al 2024 Free Rad Biol Med 217:126-140)

New infrared-based activity monitoring assays for circadian rhythms, sleep, and stress responses in zebrafish

We developed an open source software Rtivity and here we show that combined with a Locomotor Activity Monitor (LAM) researchers can assess behavioral disruptions in zebrafish larvae. Zebrafish were monitored under abnormal light conditions and exposure to the Parkinsonian toxin MPP+. Findings revealed that the LAM effectively detected circadian disruptions, such as increased activity periods and phase shifts, alongside concentration-dependent decreases in activity and sleep disruptions from MPP+. The use of LAM offers a practical, low-storage solution for high-throughput behavioral studies, paving the way for standardized methods in toxicity assessment.
(Silva et al 2022 Chemosphere 305:135449)

The interplay between mitochondria and proteostasis in Huntington’s disease

Abnormal proteostasis, dysfunctional mitochondria, and aberrant redox signalling are often associated in neurodegenerative disorders. We investigated how changes in redox signalling affect proteostasis mechanisms - including protein degradation pathways and unfolded protein responses - by testing the mitochondria-targeted antioxidant MitoQ in HD mice. We showed that abnormal redox signalling in muscle contributes to altered proteostasis and motor impairment, and that redox interventions can improve muscle performance, highlighting the importance of peripheral therapeutics in HD (Pinho et al 2020 Free Rad Biol Med 146:372-382).

Mitochondrial superoxide generation induces Parkinsonian phenotypes and Huntingtin aggregation

Superoxide generation by mitochondria is a major source of reactive oxygen species (ROS) which are capable of initiating redox signaling and oxidative damage. The current understanding of the role of mitochondrial ROS in health and disease has been limited by the lack of experimental strategies to selectively induce mitochondrial superoxide production. We performed a first in vivo study of the recently-developed mitochondria-targeted redox cycler MitoParaquat (MitoPQ) in the vertebrate zebrafish model and in a human cell model of Huntington's disease (HD). MitoPQ induced a parkinsonian phenotype in zebrafish, with decreased reflexes, spontaneous movement and dopaminergic neurodegeneration, without detectable effects on heart rate or atrioventricular coordination. In a HD cell model, MitoPQ promoted mutant huntingtin aggregation without increasing cell death. These results show that MitoPQ is a valuable tool for cellular and in vivo studies of the role of mitochondrial superoxide generation in redox biology, and as a trigger or co-stressor to model metabolic and neurodegenerative disease phenotypes (Pinho et al 2019 Free Rad Biol Med 130:318-327).