Glial swip-10expression controls systemic mitochondrial function, oxidative stress, and neuronal viability via copper ion homeostasis

神经退行性变 氧化应激 生物 蛋白质稳态 细胞生物学 氧化磷酸化 线粒体 神经保护 生物化学 疾病 神经科学 内科学 医学
作者
Peter Rodriguez,Vrinda Kalia,Chelsea Gibson,Zayna Gichi,André Rajoo,Carson D. Matier,Aidan T. Pezacki,Tong Xiao,Lucia Carvelli,Christopher J. Chang,Gary W. Miller,Andy V. Khamoui,Jana Boerner,Randy Blakely
标识
DOI:10.1101/2023.12.06.570462
摘要

Abstract Cuprous copper (Cu(I)) is an essential cofactor for enzymes supporting many cellular functions including mitochondrial respiration and suppression of oxidative stress. Neurons are particularly dependent on these pathways, with multiple neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease, associated with their dysfunction. Key features of Cu(I) contributions to neuronal health in vivo remain to be defined, owing largely to the complex processes involved in Cu(I) production, intracellular transport, and systemic redistribution. Here, we provide genetic and pharmacological evidence that swip-10 is a critical determinant of systemic Cu(I) levels in C. elegans , with deletion leading to systemic deficits in mitochondrial respiration, production of oxidative stress, and neurodegeneration. These phenotypes can be reproduced in wild-type worms by Cu(I)-specific chelation and offset in swip-10 mutants by growth on the Cu(I) enhancing molecule elesclomol, as well as by glial expression of wildtype swip-10 . MBLAC1 , the most closely related mammalian ortholog to swip-10 , encodes for a pre-mRNA processing enzyme for H3 histone, a protein whose actions surprisingly include an enzymatic capacity to produce Cu(I) via the reduction of Cu(II). Moreover, genome-wide association studies and post-mortem molecular studies implicate reductions of MBLAC1 expression in risk for AD with cardiovascular disease comorbidity. Consistent with these studies, we demonstrate that the deposition of β-amyloid plaques, an AD pathological hallmark, in worms engineered to express human Aβ 1-42, is greatly exaggerated by mutation of swip-10 . Together, these studies identify a novel glial-expressed, and pathway for Cu(I) production that may be targeted for the treatment of AD and other neurodegenerative diseases. Significance Statement Devastating neurodegenerative diseases such as Alzheimer’s disease, and Parkinson’s disease are associated with disruptions in copper (Cu) homeostasis. Alterations in Cu(I) give rise to increased oxidative stress burden, mitochondrial and metabolic dysfunction, and can accelerate production and/or potentiate toxicity of disease-associated protein aggregates. Here, using the model system Caenorhabditis elegans , we establish a role for the gene swip-10 in systemic Cu(I) homeostasis. Perturbation of this pathway in worms recapitulates biochemical, histological, and pathological features seen in human neurodegenerative disease. We reveal that these changes can be suppressed pharmacologically and arise when swip-10 expression is eliminated from glial cells. Our work implicates swip-10 and orthologs as key players in Cu(I) homeostasis that may be exploitable to treat multiple neurodegenerative diseases.
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