Carvelli, L. | bioRxiv Science

bioRxiv2026

Inhibition of macrophage neuraminidase 1 protects against immune thrombocytopenia by limiting platelet clearance

Immune thrombocytopenia purpura (ITP) is an autoimmune disorder characterized by a reduction in circulating platelet levels, primarily due to generation of autoantibodies to platelet surface antigens followed by their spleen macrophage-mediated clearance. Emerging evidence implicates neuraminidase (sialidase) enzymes including neuraminidase 1 (NEU1) in platelet clearance and ITP severity; however, the underlying cellular mechanisms remain unknown. Using tissue-specific NEU1 knockout mouse models, we studied the contribution of platelet and macrophage NEU1 to ITP pathogenesis and evaluated whether pharmacological inhibition of NEU1 could preserve platelet counts in a murine ITP model. Constitutive and macrophage-specific, but not platelet-specific, NEU1 knockout mice showed a protection against reduction of platelet counts in the passive ITP model suggesting that macrophage, but not platelet, NEU1 promotes platelet clearance. Genetic deletion or pharmacological blockade of macrophage NEU1 also reduced platelet phagocytosis by cultured macrophages in vitro. The selective NEU1 inhibitor CG33301 protected mice against anti-CD41a antibody-induced thrombocytopenia and showed a higher efficacy compared to pan neuraminidase inhibitor oseltamivir phosphate. Our results demonstrate that the macrophage pool of NEU1 plays a central role in platelet clearance by splenocytes during ITP by activating their phagocytosis and suggest that selective NEU1 inhibition may be a promising therapeutic strategy for this disease.

biochemistry↗

bioRxiv2023

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

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 Alzheimers disease (AD), Parkinsons 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 {beta}-amyloid plaques, an AD pathological hallmark, in worms engineered to express human A{beta}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 StatementDevastating neurodegenerative diseases such as Alzheimers disease, and Parkinsons 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.

neuroscience↗