Brain iron homeostasis is increasingly recognized as a potential target for the development of drug therapies for aging-related disorders. Dysregulation of iron metabolism associated with cellular damage and oxidative stress is reported as a common event in several neurodegenerative disorders such as Alzheimer 0 s, Parkinson 0 s, and Huntington 0 s diseases. Indeed, many proteins initially characterized in those diseases such as amyloid-b protein, a-synuclein, and huntingtin have been linked to iron neurochemistry. Iron plays a crucial role in maintaining normal physiological functions in the brain through its participation in many cellular functions such as mitochondrial respiration, myelin synthesis, and neurotransmitter synthesis and metabolism. However, excess iron is a potent source of oxidative damage through radical formation and because of the lack of a body-wide export system, a tight regulation of its uptake, transport and storage is crucial in fulfilling cellular functions while keeping its level below the toxicity threshold. In this review, we discuss the current knowledge on iron homeostasis in the brain and explore how alterations in brain iron metabolism affect neuronal function with emphasis on iron dysregulation in Alzheimer 0 s and Parkinson 0 s diseases. Finally, we discuss recent findings implicating iron as a diagnostic and therapeutic target for Alzheimer's and Parkinson's diseases.

Ferroptosis is an iron-dependent cell death, which is different from apoptosis, necrosis, autophagy, and other forms of cell death. The process of ferroptotic cell death is defined by the accumulation of lethal lipid species derived from the peroxidation of lipids, which can be prevented by iron chelators (e.g., deferiprone, deferoxamine) and small lipophilic antioxidants (e.g., ferrostatin, liproxstatin). This review summarizes current knowledge about the regulatory mechanism of ferroptosis and its association with several pathways, including iron, lipid, and cysteine metabolism. We have further discussed the contribution of ferroptosis to the pathogenesis of several diseases such as cancer, ischemia/reperfusion, and various neurodegenerative diseases (e.g., Alzheimer’s disease and Parkinson’s disease), and evaluated the therapeutic applications of ferroptosis inhibitors in clinics.

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Background and Purpose: Diacetyl-bis(4-methyl-3-thiosemicarbazonato)copper II (Cu II (atsm)) ameliorates neurodegeneration and delays disease progression in mouse models of amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD), yet the mechanism of action remains uncertain. Promising results were recently reported for separate Phase 1 studies in ALS patients and PD patients. Affected tissue in these disorders shares features of elevated Fe, low glutathione and increased lipid peroxidation consistent with ferroptosis, a novel form of regulated cell death. We therefore evaluated the ability of Cu II (atsm) to inhibit ferroptosis.Experimental Approach: Ferroptosis was induced in neuronal cell models by inhibition of glutathione peroxidase-4 activity with RSL3 or by blocking cystine uptake with erastin. Cell viability and lipid peroxidation were assessed and the efficacy of Cu II (atsm) was compared to the known antiferroptotic compound liproxstatin-1.Key Results: Cu II (atsm) protected against lipid peroxidation and ferroptotic lethality in primary and immortalised neuronal cell models (EC 50 : ≈130 nM, within an order of magnitude of liproxstatin-1). Ni II (atsm) also prevented ferroptosis with similar potency, whereas ionic Cu II did not. In cell-free systems, Cu II (atsm) and Ni II (atsm) inhibited Fe II -induced lipid peroxidation, consistent with these compounds quenching lipid radicals.Conclusions and Implications: The antiferroptotic activity of Cu II (atsm) could therefore be the disease-modifying mechanism being tested in ALS and PD trials. With potency in vitro approaching that of liproxstatin-1, Cu II (atsm) possesses favourable properties such as oral bioavailability and entry into the brain that make it an attractive investigational product for clinical trials of ferroptosis-related diseases.

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Anomalous hippocampal inhibition is involved in temporal lobe epilepsy, and reduced gephyrin immunoreactivity in the temporal lobe epilepsy hippocampus has been reported recently. However, the mechanisms responsible for curtailing postsynaptic gephyrin scaffolds are poorly understood. Here, we have investigated gephyrin expression in the hippocampus of patients with intractable temporal lobe epilepsy. Immunohistochemical and western blot analyses revealed irregular gephyrin expression in the cornu ammonis of patients with temporal lobe epilepsy and four abnormally spliced gephyrins lacking several exons in their G-domains were isolated. Identified temporal lobe epilepsy gephyrins have oligomerization deficits and they curtail hippocampal postsynaptic gephyrin and GABA(A) receptor α2 while interacting with regularly spliced gephyrins. We found that cellular stress (alkalosis and hyperthermia) induces exon skipping in gephyrin messenger RNA, which is responsible for curtailed postsynaptic gephyrin and GABA(A) receptor α2 scaffolds. Accordingly, we did not obtain evidence for gephyrin gene mutations in patients with temporal lobe epilepsy. Cellular stress such as alkalosis, for example arising from seizure activity, could thus facilitate the development of temporal lobe epilepsy by reducing GABA(A) receptor α2-mediated hippocampal synaptic transmission selectively in the cornu ammonis.

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Molybdenum is an essential trace element and crucial for the survival of animals. Four mammalian Mo-dependent enzymes are known, all of them harboring a pterin-based molybdenum cofactor (Moco) in their active site. In these enzymes, molybdenum catalyzes oxygen transfer reactions from or to substrates using water as oxygen donor or acceptor. Molybdenum shuttles between two oxidation states, Mo(IV) and Mo(VI). Following substrate reduction or oxidation, electrons are subsequently shuttled by either inter- or intra-molecular electron transfer chains involving prosthetic groups such as heme or iron-sulfur clusters. In all organisms studied so far, Moco is synthesized by a highly conserved multi-step biosynthetic pathway. A deficiency in the biosynthesis of Moco results in a pleitropic loss of all four human Mo-enzyme activities and in most cases in early childhood death. In this review we first introduce general aspects of molybdenum biochemistry before we focus on the functions and deficiencies of two Mo-enzymes, xanthine dehydrogenase and sulfite oxidase, caused either by deficiency of the apo-protein or a pleiotropic loss of Moco due to a genetic defect in its biosynthesis. The underlying molecular basis of Moco deficiency, possible treatment options and links to other diseases, such as neuropsychiatric disorders, will be discussed.