DeCure for Neurodegeneration with brain iron accumulation 6
DeCure's autonomous Neuro AI scientist is researching a drug-repurposing hypothesis for neurodegeneration with brain iron accumulation 6 — screening already-approved drugs against its 1-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleNeurodegeneration with brain iron accumulation 6 maps to a 1-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
No approved-drug candidate for neurodegeneration with brain iron accumulation 6 is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
What the evidence adds up to
Iron is essential for normal neurological function but also the most important inducer of reactive oxygen species. Brain iron concentrations increase with age and in many diseases. Abnormal iron accumulation in diseased brain areas has been reported in Hallervorden-Spatz syndrome, Alzheimer’s disease, Parkinson’s disease, and Friedreich’s ataxia, with strong evidence for iron-mediated oxidative damage as a primary contributor to cell death in these disorders. In neurodegeneration with brain iron accumulation, therapeutic trials have aimed at reducing cerebral iron content. A 2014 report on a 13-year-old girl with mitochondrial membrane protein-associated neurodegeneration treated with an iron-chelating agent found that highly increased brain iron content slowly decreased in the substantia nigra but remained stable for globus pallidus. The estimated iron content was higher by R2* compared to R2 and quantitative susceptibility mapping, a finding not previously observed in the brain of healthy volunteers.
Whether increased iron contributes to neurodegeneration has been considered controversial. Some recently identified anomalies in proteins linked with iron metabolism signify a critical role for iron dysregulation in neurodegeneration. HFE is an essential protein for regulating iron transport into cells; two common mutations, C282Y and H63D, cause cellular iron accumulation that can reach toxic levels. A mouse model in which the wild-type HFE gene is replaced by the H67D variant (mouse homologue of human H63D) showed elevated levels of brain iron at 3 months compared to controls, but this difference decreased at 6 months and was no longer present by 12 months. After injection with 59Fe-transferrin, no significant differences in brain iron uptake were found between genotypes, though increased 59Fe accumulation occurred in the livers of H67D mice. The similar rate of uptake for iron in the HFE mutant mice, coupled with increased iron, suggests that HFE activity is limited at the blood-brain barrier and that increased brain iron may result from altered handling including decreased export.
Iron deposition in the injured brain can occur via hemorrhage or as labile iron, which is considered more damaging. Iron accumulation has been linked to postoperative cognitive dysfunction, a common neurological complication after anaesthesia and surgery especially prevalent in the elderly. The neuroprotection of iron chelator is expected to provide a new target for management of postoperative cognitive dysfunction. Traumatic brain injury has been linked to later development of neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, chronic traumatic encephalopathy, and multiple sclerosis, with iron deposition contributing to neurotoxicity through free radical production, excitotoxicity, and inflammatory reactions.
What is still missing is a clear demonstration that reducing brain iron alters the clinical course of neurodegeneration with brain iron accumulation 6 specifically. The single-patient chelation report showed only partial and inconsistent iron reduction. No controlled trial has been completed. The HFE variant data come from mice and show only transient differences. Patient stratification by genetic subtype, age, and disease stage is absent. Funding for a properly powered, randomised trial of iron chelation in this specific disorder has not been secured.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
The Neuroscientist · 2000 · 132 citations
Iron in the Brain: An Important Contributor in Normal and Diseased States
AbstractIron is essential for normal neurological function because of its role in oxidative metabolism and because it is a cofactor in the synthesis of neurotransmitters and myelin. In the past several years, there has been increased attention to the importance of oxidative stress in the central nervous system. Iron is the most important inducer of reactive oxygen species, therefore, the relation of iron to neurodegenerative processes is more appreciated today than it was a few years ago. Nevertheless, despite this increased attention and awareness, our knowledge of iron metabolism in the brain at the cellular and molecular levels is still limited. Iron is distributed in a heterogeneous fashion among the different regions and cells of the brain. This regional and cellular heterogeneity is preserved across many species. Brain iron concentrations are not static; they increase with age and in many diseases and decrease when iron is deficient in the diet. In infants and children, insufficient iron in the diet is associated with decreased brain iron and with changes in behavior and cognitive functioning. Abnormal iron accumulation in the diseased brain areas and, in some cases, alterations in iron-related proteins have been reported in many neurodegenerative diseases, including Hallervorden-Spatz syndrome, Alzheimer’s disease, Parkinson’s disease, and Friedreich’s ataxia. There is strong evidence for iron-mediated oxidative damage as a primary contributor to cell death in these disorders. Demyelinating diseases, such as multiple sclerosis, especially warrant study in relation to iron availability. Myelin synthesis and maintenance have a high iron requirement, thus, oligodendrocytes must have a relatively high and constant supply of iron. However, the high oxygen utilization, high density of lipids, and high iron content of white matter all combine to increase the risk of oxidative damage. We review here the current knowledge of the normal metabolism of iron in the brain and the suspected role of iron in neuropathology.
Frontiers in Neuroscience · 2018 · 110 citations · open access
The Involvement of Iron in Traumatic Brain Injury and Neurodegenerative Disease
AbstractTraumatic brain injury (TBI) consists of acute and long-term pathophysiological sequelae that ultimately lead to cognitive and motor function deficits, with age being a critical risk factor for poorer prognosis. TBI has been recently linked to the development of neurodegenerative diseases later in life including Alzheimer's disease, Parkinson's disease, chronic traumatic encephalopathy, and multiple sclerosis. The accumulation of iron in the brain has been documented in a number of neurodegenerative diseases, and also in normal aging, and can contribute to neurotoxicity through a variety of mechanisms including the production of free radicals leading to oxidative stress, excitotoxicity and by promoting inflammatory reactions. A growing body of evidence similarly supports a deleterious role of iron in the pathogenesis of TBI. Iron deposition in the injured brain can occur via hemorrhage/microhemorrhages (heme-bound iron) or independently as labile iron (non-heme bound), which is considered to be more damaging to the brain. This review focusses on the role of iron in potentiating neurodegeneration in TBI, with insight into the intersection with neurodegenerative conditions. An important implication of this work is the potential for therapeutic approaches that target iron to attenuate the neuropathology/phenotype related to TBI and to also reduce the associated risk of developing neurodegenerative disease.
Iron Dysregulation and Neurodegeneration: The Molecular Connection
AbstractIron is essential for many biological processes however excess concentrations can be harmful to many tissues. Its amounts must therefore be carefully regulated in all cells of the body including those in the brain. Increased amounts of iron have been reported in many neurodegenerative disorders. Whether this increased iron contributes to neurodegeneration has been considered controversial. In this review, we discuss some recently identified anomalies in proteins linked with iron metabolism which signify a critical role for iron dysregulation in neurodegeneration.
International Journal of Cell Biology · 2012 · 80 citations · open access
Chelators in the Treatment of Iron Accumulation in Parkinson's Disease
AbstractIron is an essential element in the metabolism of all cells. Elevated levels of the metal have been found in the brains of patients of numerous neurodegenerative disorders, including Parkinson's disease (PD). The pathogenesis of PD is largely unknown, although it is thought through studies with experimental models that oxidative stress and dysfunction of brain iron homeostasis, usually a tightly regulated process, play significant roles in the death of dopaminergic neurons. Accumulation of iron is present at affected neurons and associated microglia in the substantia nigra of PD patients. This additional free-iron has the capacity to generate reactive oxygen species, promote the aggregation of α-synuclein protein, and exacerbate or even cause neurodegeneration. There are various treatments aimed at reversing this pathologic increase in iron content, comprising both synthetic and natural iron chelators. These include established drugs, which have been used to treat other disorders related to iron accumulation. This paper will discuss how iron dysregulation occurs and the link between increased iron and oxidative stress in PD, including the mechanism by which these processes lead to cell death, before assessing the current pharmacotherapies aimed at restoring normal iron redox and new chelation strategies undergoing research.
Annals of Clinical and Translational Neurology · 2014 · 27 citations · open access
Brain iron quantification by MRI in mitochondrial membrane protein‐associated neurodegeneration under iron‐chelating therapy
AbstractTherapeutic trials for Neurodegeneration with Brain Iron Accumulation have aimed at a reduction of cerebral iron content. A 13-year-old girl with mitochondrial membrane protein-associated neurodegeneration treated with an iron-chelating agent was monitored by R2 relaxometry, R2* relaxometry, and quantitative susceptibility mapping to estimate the brain iron content. The highly increased brain iron content slowly decreased in the substantia nigra but remained stable for globus pallidus. The estimated iron content was higher by R2* compared to R2 and quantitative susceptibility mapping, a finding not previously observed in the brain of healthy volunteers. A hypothesis explaining this discrepancy is offered.
The role of iron accumulation in postoperative cognitive dysfunction
AbstractBackground Postoperative cognitive dysfunction (POCD) is a common neurological complication after anesthesia and surgery,especially prevalent in the elderly.Iron accumulation in the brain is an initial cause of neurodegeneration,it gives rise to neuronal degeneration and necrosis by arousing oxidative stress.Objective This review aims to investigate the role of iron accumulation in POCD.Content The distribution of brain iron,iron metabolism protein function,the relationship of excessive iron levels in the brain and neurodegeneration,as well as the progress of iron accumulation in POCD are described in the article.Trend Iron accumulation may be an important mechanism of POCD,the neuroprotection of iron chelator is expected to provide new target for the management of POCD.
Key words:
Iron accumulation; Neurodegeneration; Postoperative cognitive dysfunction
The Role of a Common HFE Gene Variant in Brain Iron Accumulation
AbstractHFE is an essential protein for regulating iron transport into cells. Two common mutations of HFE, C282Y and H63D, result in loss of this regulation and cause accumulation of iron within the cell. The cellular iron accumulation can reach toxic levels. While much has been studied regarding the role of HFE in iron uptake, it has remained unclear what role the protein plays in the transport of iron into the brain. In fact, it has long been believed that the brain is protected against iron overload by the blood‐brain barrier (BBB). Recently, however, our laboratory and others have correlated HFE gene variants with neurodegenerative diseases, specifically amyotrophic lateral sclerosis (ALS) and Alzheimer's Disease (AD). A critical review of historic literature, recent MRI studies and a novel more representative mouse model generated in our laboratory all suggest there is elevated iron in the brain associated with HFE gene variants. We generated a mouse model in which the wild‐type (WT) HFE gene is replaced by the H67D gene variant (mouse homologue of the human H63D gene variant). There are elevated levels of brain iron in 3 month old mice with the H67D mutation when compared to their controls, but this difference in levels is decreased at 6 months and no longer present by 12 months of age. Here, we performed an in vivo study to identify brain iron uptake and distribution patterns in 3 month old WT and H67D mice. After injection with 59 Fe‐transferrin, mice were sacrificed at 24 hours and 5 days post‐injection. 59 Fe levels measured in brain homogenate and isolated microvessels showed no significant differences between genotypes. There was, however, increased 59 Fe accumulation in the livers of H67D mice. This study makes two novel discoveries. First, there is iron accumulation in the microvessels in the brain supporting the concept put forth recently by our group that the BBB is not a conduit but a regulatory site for brain iron uptake. Secondly, the similar rate of uptake for iron in the HFE mutant mice, coupled with the increased amount of iron suggests that the activity of the HFE protein is limited at the BBB. The increased iron in the brain in the H67D mice may be the result of altered handling of the iron including decreased export. We cannot rule out the lack of difference in uptake is a compensatory process already in place because of the higher iron levels and this notion is under investigation. The apparent ability of the BBB, unlike the liver for example, to adapt to the HFE gene variant reinforces the importance of understanding the mechanisms and regulation of brain iron uptake and how the pathway is modulated in the diseased brain. Support or Funding Information This work was supported by NIH P01 AG021190 and P01 HD39386.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
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