Cerebral Iron Deposition in Neurodegeneration

Disruption of cerebral iron regulation appears to have a role in aging and in the pathogenesis of various neurodegenerative disorders. Possible unfavorable impacts of iron accumulation include reactive oxygen species generation, induction of ferroptosis, and acceleration of inflammatory changes. Whole-brain iron-sensitive magnetic resonance imaging (MRI) techniques allow the examination of macroscopic patterns of brain iron deposits in vivo, while modern analytical methods ex vivo enable the determination of metal-specific content inside individual cell-types, sometimes also within specific cellular compartments. The present review summarizes the whole brain, cellular, and subcellular patterns of iron accumulation in neurodegenerative diseases of genetic and sporadic origin. We also provide an update on mechanisms, biomarkers, and effects of brain iron accumulation in these disorders, focusing on recent publications. In Parkinson’s disease, Friedreich’s disease, and several disorders within the neurodegeneration with brain iron accumulation group, there is a focal siderosis, typically in regions with the most pronounced neuropathological changes. The second group of disorders including multiple sclerosis, Alzheimer’s disease, and amyotrophic lateral sclerosis shows iron accumulation in the globus pallidus, caudate, and putamen, and in specific cortical regions. Yet, other disorders such as aceruloplasminemia, neuroferritinopathy, or Wilson disease manifest with diffuse iron accumulation in the deep gray matter in a pattern comparable to or even more extensive than that observed during normal aging. On the microscopic level, brain iron deposits are present mostly in dystrophic microglia variably accompanied by iron-laden macrophages and in astrocytes, implicating a role of inflammatory changes and blood–brain barrier disturbance in iron accumulation. Options and potential benefits of iron reducing strategies in neurodegeneration are discussed. Future research investigating whether genetic predispositions play a role in brain Fe accumulation is necessary. If confirmed, the prevention of further brain Fe uptake in individuals at risk may be key for preventing neurodegenerative disorders.publishedVersio

CHARACTERIZATION OF BIODISTRIBUTION OF TRANSFERRIN AND RECEPTOR BINDING MECHANISM BY MASS SPECTROMETRY

Protein-based therapeutics have emerged as a key driver of rapid growth in drug development pipelines. However, developing such protein drugs is not straightforward in most cases, the existence of physiological barriers greatly restricts the efficient delivery of many therapeutic molecules, and therefore limits their clinical applications. A promising way to address this challenge takes advantage of certain transport protein which can effectively across and enhance the permeability of these barriers, such as transferrin (Tf) which can be internalized by malignant cells and cross physiological barriers via transferrin receptor (TfR)-mediated endocytosis and transcytosis. However, developing such products is impossible without successfully understanding the molecular mechanisms governing Tf/TfR interactions and the ability to monitor the biodistribution of Tf. In this work, hydrogen/deuterium exchange mass spectrometry (HDX MS) is used to investigate TfR higher order structural and dynamic changes in different Tf/TfR models that mimic various stages encountered during endocytosis. Detailed characterizations of TfR gained by HDX MS reveal the regions located at the interdomain cleft exhibiting bimodal exchange patterns may be responsible for the loss of its enzyme function in the molecular evolution. At neutral pH, a movement at the TfR/TfR interface helps to stabilize the holoTf/TfR complexation. At acidic pH, the pH-induced conformational changes at the TfR helical domain trigger a series of movements that lead to specific binding properties for holo- and apoTf C-lobe. Obtaining this information greatly enhances our understanding of the pH-dependent Tf binding properties and how TfR facilitates iron release at acidic pH. Another aspect of this dissertation work is utilizing the ability of Tf to bind to noncognate metals to trace the biodistribution of Tf. Particularly, indium has been evaluated and demonstrated as an ideal tracer of exogenous Tf in complex biological matrices using inductively coupled plasma mass spectrometry (ICP MS) as a detection tool. In addition, combining laser ablation (LA) with ICP MS detection allows distribution of exogenous Tf to be mapped within animal tissue cross-sections. The high sensitivity and selectivity of this novel approach make it an ideal quantitation/imaging tool for in vivo studies of biodistribution of Tf and Tf-based therapeutics