Brain iron enrichment attenuates α‐synuclein spreading after injection of preformed fibrils

Joppe, Karina; Tatenhorst, Lars; Gomes, Lucas Caldi; Zhang, Shuyu; Parvaz, Mojan; Carboni, Eleonora; Roser, Anna-Elisa; DeBakey, Hazem El; Bähr, Mathias; Vogel‐Mikuš, Katarina; Ip, Chi Wang; Becker, Stefan; Zweckstetter, Markus; Lingor, Paul

doi:10.1111/jnc.15461

Cited by 16 publications

(16 citation statements)

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“…A previous study showed that intranasal injection of αsynuclein PFFs induced microglial iron deposition in monkeys (Guo et al, 2021). Combining the results of these two recent studies, where α-synuclein was shown to induce iron accumulation (Guo et al, 2021) but the iron elevation was shown to slow α-synuclein spreading (Joppe et al, 2021), suggests that α-synuclein may precede the iron accumulation during the progress of PD.…”

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confidence: 78%

“…Lewy body pathology has been shown to be transmitted between brain regions (Hijaz & Volpicelli‐Daley, 2020), it remains unknown what impact iron may have on this pathology spreading. In a recent study published in the Journal of Neurochemistry , Joppe and colleagues (Joppe et al., 2021) found that in a mouse model of intrastriatal α‐synuclein preformed fibrils (PFFs) injection, the propagation of pathological α‐synuclein marked as α‐synuclein phosphorylated at serine 129 (pS129) was decreased in mice that had brain iron elevation induced by neonatal iron feeding (Figure 1). The long‐term memory but not motor function showed impairment at 90 days after α‐synuclein PFFs injection with or without iron feeding.…”

Section: Figurementioning

confidence: 99%

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Iron reduces the propagation of pathological α‐synuclein

Guo

Ayton

Lei

2021

Journal of Neurochemistry

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Elevated iron and pathological α-synuclein (the main component of Lewy bodies) are common features of Parkinson's disease (PD), however, whether they are mechanistically related is uncertain.α-synuclein has been shown to bind to iron in vitro, which accelerates its aggregation into fibrils (Golts et al., 2002). Iron enrichment of Lewy bodies reveals the potential for this interaction to be of pathological significance (Ayton & Lei, 2014). It is possible that iron may interact with α-synuclein to cause neurodegeneration in PD by the iron-dependent cell death pathway termed ferroptosis (Yan et al., 2021). While aggregated α-synuclein was shown not to induce ferroptosis in neuroblastoma cells (Guiney et al., 2020), and α-synuclein toxicity was abolished by inhibitors of ferroptosis in induced pluripotent stem cell (iPSC)-derived neurons (Angelova et al., 2020). Lewy body pathology has been shown to be transmitted between brain regions (Hijaz & Volpicelli-Daley, 2020), it remains unknown what impact iron may have on this pathology spreading. In a recent study published in the Journal of Neurochemistry, Joppe and colleagues (Joppe et al., 2021) found that in a mouse model of intrastriatal α-synuclein preformed fibrils (PFFs) injection, the propagation of pathological α-synuclein marked as αsynuclein phosphorylated at serine 129 (pS129) was decreased in mice that had brain iron elevation induced by neonatal iron feeding (Figure 1). The long-term memory but not motor function

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mentioning

confidence: 78%

Section: Figurementioning

confidence: 99%

Iron reduces the propagation of pathological α‐synuclein

Guo

Ayton

Lei

2021

Journal of Neurochemistry

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“…Moreover, PD patients show elevated Fe levels both in the NM neurons and immediately adjacent surrounding tissue (Oakley et al., 2007). Interestingly, iron interacts with alpha‐synuclein (reviewed in Lingor et al., 2017; Joppe et al., 2019) and an increase in brain iron alters alpha‐synuclein aggregation (Dauer Née Joppe et al., 2021). There is thus compelling evidence of Fe accumulation in the SN of PD patients, and this excess Fe can be visualized using magnetic resonance imaging (MRI) (Li et al., 2022).…”

Section: Discussionmentioning

confidence: 99%

Metal dyshomeostasis in the substantia nigra of patients with Parkinson's disease or multiple sclerosis

Carmona,

Carboni,

Gomes

et al. 2024

Journal of Neurochemistry

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Abnormal metal distribution in vulnerable brain regions is involved in the pathogenesis of most neurodegenerative diseases, suggesting common molecular mechanisms of metal dyshomeostasis. This study aimed to compare the intra‐ and extra‐neuronal metal content and the expression of proteins related to metal homeostasis in the substantia nigra (SN) from patients with Parkinson's disease (PD), multiple sclerosis (MS), and control subjects. Metal quantification was performed via ion‐beam micro‐analysis in neuromelanin‐positive neurons and the surrounding tissue. For proteomic analysis, SN tissue lysates were analyzed on a nanoflow chromatography system hyphenated to a hybrid triple‐quadrupole time‐of‐flight mass spectrometer. We found increased amounts of iron in neuromelanin‐positive neurons and surrounding tissue in patients with PD and MS compared to controls (4‐ to 5‐fold higher) that, however, also showed large inter‐individual variations. Copper content was systematically lower (−2.4‐fold) in neuromelanin‐positive neurons of PD patients compared with controls, whereas it remained unchanged in MS. Protein–protein interaction (PPI) network analyses revealed clusters related to Fe and Cu homeostasis among PD‐deregulated proteins. An enrichment for the term “metal homeostasis” was observed for MS‐deregulated proteins. Important deregulated hub proteins included hemopexin and transferrin in PD, and calreticulin and ferredoxin reductase in MS. Our findings show that PD and MS share commonalities in terms of iron accumulation in the SN. Concomitant proteomics experiments revealed PPI networks related to metal homeostasis, substantiating the results of metal quantification.

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“…However, the link between iron and α‐syn goes deeper than this. A recent study reported that iron enrichment occurring in particular areas of PD brains affected the spreading pathology of α‐syn in mice models 180 . Striatal iron retention alters the connectivity of the brain connectome, leading to a redistribution of α‐syn aggregates in the brain, or rather the restriction of phosphorylated α‐syn spread.…”

Section: Iron Metabolism In Brain Diseasesmentioning

confidence: 99%

Iron homeostasis imbalance and ferroptosis in brain diseases

Long

Zhu

Wei

et al. 2023

MedComm

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Brain iron homeostasis is maintained through the normal function of blood–brain barrier and iron regulation at the systemic and cellular levels, which is fundamental to normal brain function. Excess iron can catalyze the generation of free radicals through Fenton reactions due to its dual redox state, thus causing oxidative stress. Numerous evidence has indicated brain diseases, especially stroke and neurodegenerative diseases, are closely related to the mechanism of iron homeostasis imbalance in the brain. For one thing, brain diseases promote brain iron accumulation. For another, iron accumulation amplifies damage to the nervous system and exacerbates patients’ outcomes. In addition, iron accumulation triggers ferroptosis, a newly discovered iron‐dependent type of programmed cell death, which is closely related to neurodegeneration and has received wide attention in recent years. In this context, we outline the mechanism of a normal brain iron metabolism and focus on the current mechanism of the iron homeostasis imbalance in stroke, Alzheimer's disease, and Parkinson's disease. Meanwhile, we also discuss the mechanism of ferroptosis and simultaneously enumerate the newly discovered drugs for iron chelators and ferroptosis inhibitors.

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Brain iron enrichment attenuates α‐synuclein spreading after injection of preformed fibrils

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmerc ial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 16 publications

References 121 publications

Iron reduces the propagation of pathological α‐synuclein

Iron reduces the propagation of pathological α‐synuclein

Metal dyshomeostasis in the substantia nigra of patients with Parkinson's disease or multiple sclerosis

Iron homeostasis imbalance and ferroptosis in brain diseases

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