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

Abstract

AbstractCuprous 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 healthin vivoremain 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 thatswip-10is a critical determinant of systemic Cu(I) levels inC. 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 inswip-10mutants by growth on the Cu(I) enhancing molecule elesclomol, as well as by glial expression of wildtypeswip-10.MBLAC1, the most closely related mammalian ortholog toswip-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 ofMBLAC1expression 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 Aβ1-42,is greatly exaggerated by mutation ofswip-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 StatementDevastating 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 systemCaenorhabditis elegans, we establish a role for the geneswip-10in 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 whenswip-10expression is eliminated from glial cells. Our work implicatesswip-10and orthologs as key players in Cu(I) homeostasis that may be exploitable to treat multiple neurodegenerative diseases.