Alterations in Metal Homeostasis Occur Prior to Canonical Markers in Huntington Disease

Objective: The importance of metal biology in neurodegenerative diseases such as Huntingtin Disease is well documented with evidence of direct interactions between metals such as copper, zinc, iron and manganese and mutant Huntingtin pathobiology. To date, it is unclear whether these interactions are observed in humans, how this impacts other metals, and how mutant Huntington alters homeostatic mechanisms governing levels of copper, zinc, iron and manganese in cerebrospinal fluid and blood in HD patients.Methods: Plasma and cerebrospinal fluid from control, pre-manifest, manifest and late manifest HD participants were collected as part of HD-Clarity. Levels of cerebrospinal fluid and plasma copper, zinc, iron and manganese were measured as well as levels of mutant Huntingtin and neurofilament in a sub-set of cerebrospinal fluid samples.Results: We find that elevations in cerebrospinal fluid copper, manganese and zinc levels are altered early in disease prior to alterations in canonical biomarkers of HD although these changes are not present in plasma. We also evidence that CSF iron is elevated in manifest patients. The relationships between plasma and cerebrospinal fluid metal are altered based on disease stage.Interpretation: These findings demonstrate that there are alterations in metal biology selectively in the CSF which occur prior to changes in known canonical biomarkers of disease. Our work indicates that there are pathological changes related to alterations in metal biology in individuals without elevations in neurofilament and mutant Huntingtin.

mSphere of Influence: an Army Marching on Its Stomach—Malaria Parasites Sense and Subvert Host Nutrition

ABSTRACT Clare Harding works on the metal biology of the parasite Toxoplasma gondii. In this mSphere of Influence article, she reflects on how two papers from the laboratory of Maria Mota, “Host-mediated regulation of superinfection in malaria” by Portugal et al. (S. Portugal, C. Carret, M. Recker, A. E. Armitage, et al., Nat Med 17:732–737, 2011, https://doi.org/10.1038/nm.2368) and “Nutrient sensing modulates malaria parasite virulence” by Mancio-Silva et al. (L. Mancio-Silva, K. Slavic, M. T. Grilo Ruivo, A. R. Grosso, et al., Nature 547:213–216, 2017, https://doi.org/10.1038/nature23009), made an impact on her understanding of host-pathogen interactions by examining the complex interplay between parasites and their hosts’ nutritional status.

Synthetic fluorescent probes for studying copper in biological systems

This review surveys fluorescent probes for copper, emphasizing desirable criteria for their effective use for discovery and study of new metal biology.