Retrospective Study of the Physiological and Molecular Features of the S-FUS (1-359) Mouse Transgenic Model with an ALS-like Phenotype: Lifespan, Body Weight Dynamics, Movement Disorders, and Dysregulation of the Dopaminergic System.

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease leading to disability and death. Genetic animal models, like transgenic mice, are critical for studying disease mechanisms and developing therapies. Model validity, experimental standardization, and predictability are key to successful research. This retrospective study analyzed physiological parameters of the S-FUS (1-359) transgenic mouse model over 10 years, focusing on lifespan, body weight dynamics, symptomatic stages, and molecular changes. Hemizygous mice had a mean lifespan of 137.8 days (males) and 125.1 days (females), longer than homozygous counterparts. The symptomatic stage, marked by motor deficits, began at ~ 123 days and lasted 10-15 days. Body weight loss correlated with disease progression, reaching 28.93% of baseline at death. Molecular analysis revealed regional FUS expression differences (midbrain > spinal cord), alongside proinflammatory cytokine activation (Il6, Tnf alpha) and oxidative stress. Dopaminergic dysregulation was evident, with striatal dopamine/metabolite levels rising 40-60%, linked to Maob downregulation and impaired GABAergic inhibition. Midbrain-selective caspase-3 suppression suggested a shift from apoptosis to necroptosis, while spinal cord astrogliosis indicated compensatory mechanisms. Heterogeneity in lifespan, symptom onset timing, and disease duration was observed, underscoring the need for rigorous experimental design, particularly for therapies aiming to delay symptoms or extend survival. Dopamine oxidation emerged as a novel neurotoxicity contributor, highlighting potential therapeutic targets: modulating dopaminergic signaling and reducing oxidative stress.