Coenzyme A (CoA) is a vital cofactor involved in energy metabolism, lipid biosynthesis, protein modification, and epigenetic regulation. Disruptions in CoA biosynthesis have been implicated in neurometabolic disorders such as pantothenate kinase-associated neurodegeneration (PKAN) and COASY protein-associated neurodegeneration (CoPAN), both within the heterogeneous spectrum of Neurodegeneration with Brain Iron Accumulation (NBIA). Specifically, CoPAN results from recessive variants in the COASY gene, encoding the bifunctional CoA synthase enzyme, leading to progressive neurodegeneration, motor impairment, and metabolic abnormalities. To investigate the neuronal impact of CoA deficiency, we developed an inducible, neuron-specific Coasy deleted mouse model. Unlike previous constitutive models, this system faithfully recapitulates key clinical and molecular features of CoPAN, including motor deficits, neurodegeneration, iron dyshomeostasis, and reduced survival. Strikingly, conditional neuronal Coasy ablation triggered extensive and progressive neuroinflammation, highlighting a neglected pathogenic component and potential therapeutic target. This model thus represents a robust platform to dissect disease mechanisms and evaluate candidate treatments. Given the established neuroprotective role of peroxisome proliferator-activated receptor gamma (PPARγ), we tested leriglitazone, a novel brain-penetrant full and selective PPARγ agonist effective in other rare neurodegenerative models. Leriglitazone treatment significantly improved motor performance, restored iron homeostasis, and attenuated both neuroinflammation and neurodegeneration. This study advances our understanding of the mechanism driving CoA-related neurodegeneration, highlights neuroinflammation as a pivotal pathogenic process, and demonstrates the therapeutic potential of PPARγ activation, underscoring leriglitazone as a promising candidate for CoPAN and potentially for the broader NBIA spectrum. • The inducible, conditional Coasy neuronal deleted model mirrors CoPAN, exhibiting movement disorders, reduced lifespan, iron dyshomeostasis, and progressive neurodegeneration. • Neuroinflammation emerges as a key contributor to CoA-related neurodegeneration. • PPARγ agonist leriglitazone improves motor function, restores iron balance, and reduces neuroinflammatory and neurodegenerative pathology in Coasy mouse model. • PPARγ activation may provide a potential therapeutic approach for NBIA disorders.
Cavestro et al. (Wed,) studied this question.