4 research outputs found
The Contribution of Iron to Protein Aggregation Disorders in the Central Nervous System
The homeostasis of iron is of fundamental importance in the central nervous system (CNS) to ensure biological processes such as oxygen transport, mitochondrial respiration or myelin synthesis. Dyshomeostasis and accumulation of iron can be observed during aging and both are shared characteristics of several neurodegenerative diseases. Iron-mediated generation of reactive oxygen species (ROS) may lead to protein aggregation and cellular toxicity. The process of misfolding and aggregation of neuronal proteins such as α-synuclein, Tau, amyloid beta (AÎČ), TDP-43 or SOD1 is a common hallmark of many neurodegenerative disorders and iron has been shown to facilitate protein aggregation. Thus, both, iron and aggregating proteins are proposed to amplify their detrimental effects in the disease state. In this review, we give an overview on effects of iron on aggregation of different proteins involved in neurodegeneration. Furthermore, we discuss the proposed mechanisms of iron-mediated toxicity and protein aggregation emphasizing the red-ox chemistry and protein-binding properties of iron. Finally, we address current therapeutic approaches harnessing iron chelation as a disease-modifying intervention in neurodegenerative disorders, such as Parkinsonâs disease, Alzheimerâs disease, and amyotrophic lateral sclerosis
Elemental quantification and analysis of structural abnormalities in neurons from Parkinsonâs-diseased brains by X-ray fluorescence microscopy and diffraction
International audienc
Brain iron enrichment attenuates 뱉synuclein spreading after injection of preformed fibrils
Regional iron accumulation and αâsynuclein (αâsyn) spreading pathology within the central nervous system are common pathological findings in Parkinson's disease (PD). Whereas iron is known to bind to αâsyn, facilitating its aggregation and regulating αâsyn expression, it remains unclear if and how iron also modulates αâsyn spreading. To elucidate the influence of iron on the propagation of αâsyn pathology, we investigated αâsyn spreading after stereotactic injection of αâsyn preformed fibrils (PFFs) into the striatum of mouse brains after neonatal brain iron enrichment. C57Bl/6J mouse pups received oral gavage with 60, 120, or 240 mg/kg carbonyl iron or vehicle between postnatal days 10 and 17. At 12 weeks of age, intrastriatal injections of 5â”g PFFs were performed to induce seeding of αâsyn aggregates. At 90 days postâinjection, PFFsâinjected mice displayed longâterm memory deficits, without affection of motor behavior. Interestingly, quantification of αâsyn phosphorylated at S129 showed reduced αâsyn pathology and attenuated spreading to connectomeâspecific brain regions after brain iron enrichment. Furthermore, PFFs injection caused intrastriatal microglia accumulation, which was alleviated by iron in a doseâdependent way. In primary cortical neurons in a microfluidic chamber model in vitro, iron application did not alter transâsynaptic αâsyn propagation, possibly indicating an involvement of nonâneuronal cells in this process. Our study suggests that αâsyn PFFs may induce cognitive deficits in mice independent of iron. However, a redistribution of αâsyn aggregate pathology and reduction of striatal microglia accumulation in the mouse brain may be mediated via ironâinduced alterations of the brain connectome