Conservative iron chelation for neurodegenerative diseases such as Parkinson’s disease and amyotrophic lateral sclerosis

Devos, David; Cabantchik, Z. Ioav; Moreau, Caroline; Danel, Véronique; Mahoney-Sánchez, Laura; Bouchaoui, Hind; Gouel, Flore; Rolland, Anne‐Sophie; Duce, James A.; Devedjian, Jean-Christophe

doi:10.1007/s00702-019-02138-1

Cited by 83 publications

(59 citation statements)

References 105 publications

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“…Convergent evidence suggests that intervention to prevent iron overload in the SNpc may be a promising disease modifying approach [40]. Regional increase of iron in the SNpc of PD patients has been robustly documented in independent studies [7,[41][42][43][44] and further substantiated by a recent meta-analysis [45]. Consistently, recent clinical trials demonstrated the efficacy of the iron chelator deferiprone [13,15].…”

Section: Discussionmentioning

confidence: 84%

Gender biased neuroprotective effect of Transferrin Receptor 2 deletion in multiple models of Parkinson’s disease

et al. 2020

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Alterations in the metabolism of iron and its accumulation in the substantia nigra pars compacta accompany the pathogenesis of Parkinson’s disease (PD). Changes in iron homeostasis also occur during aging, which constitutes a PD major risk factor. As such, mitigation of iron overload via chelation strategies has been considered a plausible disease modifying approach. Iron chelation, however, is imperfect because of general undesired side effects and lack of specificity; more effective approaches would rely on targeting distinctive pathways responsible for iron overload in brain regions relevant to PD and, in particular, the substantia nigra. We have previously demonstrated that the Transferrin/Transferrin Receptor 2 (TfR2) iron import mechanism functions in nigral dopaminergic neurons, is perturbed in PD models and patients, and therefore constitutes a potential therapeutic target to halt iron accumulation. To validate this hypothesis, we generated mice with targeted deletion of TfR2 in dopaminergic neurons. In these animals, we modeled PD with multiple approaches, based either on neurotoxin exposure or alpha-synuclein proteotoxic mechanisms. We found that TfR2 deletion can provide neuroprotection against dopaminergic degeneration, and against PD- and aging-related iron overload. The effects, however, were significantly more pronounced in females rather than in males. Our data indicate that the TfR2 iron import pathway represents an amenable strategy to hamper PD progression. Data also suggest, however, that therapeutic strategies targeting TfR2 should consider a potential sexual dimorphism in neuroprotective response.

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Section: Discussionmentioning

confidence: 84%

Gender biased neuroprotective effect of Transferrin Receptor 2 deletion in multiple models of Parkinson’s disease

et al. 2020

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“…Although iron can be exported through other mechanisms, efflux via ferroportin, which requires oxidation of iron by ceruloplasmin, constitutes a major pathway in some cells. Thus, decreased copperdependent ferroxidase activity could contribute to the accumulation iron, which has been identified in ALS patients by magnetic resonance imaging 22 . Similarly, catecholamines are essential for neuronal function and DbH is an important part of their regulation because it converts dopamine to norepinephrine.…”

Section: Discussionmentioning

confidence: 97%

Disrupted copper availability in sporadic ALS: Implications for Cu^II(atsm) as a treatment option

Hilton

Kysenius

Liddell

et al. 2020

Preprint

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Objective: The copper compound Cu II (atsm) is in phase 2/3 testing for treatment of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Cu II (atsm) consistently and reproducibly ameliorates neurodegeneration in mutant SOD1 mouse models of ALS where its neuroprotective activity has been ascribed in part to improving availability of copper to essential cuproenzymes. However, SOD1 mutations cause only ~2% of ALS cases with most cases being of unknown aetiology. Therapeutic pertinence of Cu II (atsm) to sporadic ALS is therefore unclear. Methods:We assayed post-mortem spinal cord tissue from sporadic cases of ALS for the anatomical and biochemical distribution of copper, the expression of genes involved in copper handling, and the activities of cuproenzymes. Results:The natural distribution of copper is disrupted in sporadic ALS. The ALS-affected tissue has a molecular signature consistent with an unsatiated requirement for copper and cuproenzyme activity is affected. Copper levels are decreased in the ventral grey matter, the primary anatomical site of neuronal loss in ALS.Interpretation: Mice expressing mutant SOD1 recapitulate salient features of ALS. The unsatiated requirement for copper that is evident in these mice is a biochemical target for Cu II (atsm). Evidences provided here for disrupted copper bioavailability in human cases of sporadic ALS indicate that a therapeutic mechanism for Cu II (atsm) involving copper bioavailability is pertinent to sporadic cases of ALS, and not just those involving mutant SOD1.

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“…Recently, researchers found that in PD patients, iron and hydroxyl radical levels in the substantia nigra are increased, leading to damage of DA neurons. Besides, other ferroptosis characteristics such as GSH depletion have also been observed in the substantia nigra of PD patients (Zhao, 2019 ; Devos et al, 2020 ; Zhang et al, 2020 ). Another study reported that loss of plasma ceruloplasmin iron oxidase activity in the substantia nigra of PD patients, which led to the accumulation of iron peroxide.…”

Section: Ferroptosis and Nervous System Diseasesmentioning

confidence: 99%

Insight Into the Role of Ferroptosis in Non-neoplastic Neurological Diseases

Lei

Chen

Song

et al. 2020

Front. Cell. Neurosci.

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Ferroptosis is an iron-dependent form of cell death characterized by the accumulation of intracellular lipid reactive oxygen species (ROS). Ferroptosis is significantly different from other types of cell death including apoptosis, autophagy, and necrosis, both in morphology and biochemical characteristics. The mechanisms that are associated with ferroptosis include iron metabolism, lipid oxidation, and other pathophysiological changes. Ferroptosis inducers or inhibitors can influence its occurrence through different pathways. Ferroptosis was initially discovered in tumors, though recent studies have confirmed that it is also closely related to a variety of neurological diseases including neurodegenerative disease [Alzheimer's disease (AD), Parkinson's disease (PD), etc.] and stroke. This article reviews the definition and characteristics of ferroptosis, the potential mechanisms associated with its development, inducers/inhibitors, and its role in non-neoplastic neurological diseases. We hope to provide a theoretical basis and novel treatment strategies for the treatment of central nervous system diseases by targeting ferroptosis.

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Conservative iron chelation for neurodegenerative diseases such as Parkinson’s disease and amyotrophic lateral sclerosis

Cited by 83 publications

References 105 publications

Gender biased neuroprotective effect of Transferrin Receptor 2 deletion in multiple models of Parkinson’s disease

Gender biased neuroprotective effect of Transferrin Receptor 2 deletion in multiple models of Parkinson’s disease

Disrupted copper availability in sporadic ALS: Implications for Cu^II(atsm) as a treatment option

Insight Into the Role of Ferroptosis in Non-neoplastic Neurological Diseases

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Conservative iron chelation for neurodegenerative diseases such as Parkinson’s disease and amyotrophic lateral sclerosis

Cited by 83 publications

References 105 publications

Gender biased neuroprotective effect of Transferrin Receptor 2 deletion in multiple models of Parkinson’s disease

Gender biased neuroprotective effect of Transferrin Receptor 2 deletion in multiple models of Parkinson’s disease

Disrupted copper availability in sporadic ALS: Implications for CuII(atsm) as a treatment option

Insight Into the Role of Ferroptosis in Non-neoplastic Neurological Diseases

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Disrupted copper availability in sporadic ALS: Implications for Cu^II(atsm) as a treatment option