TY - JOUR
T1 - Conservative iron chelation for neurodegenerative diseases such as Parkinson’s disease and amyotrophic lateral sclerosis
AU - The FAIRPARK-II and FAIRALS-II studygroups
AU - Devos, David
AU - Cabantchik, Z. Ioav
AU - Moreau, Caroline
AU - Danel, Véronique
AU - Mahoney-Sanchez, Laura
AU - Bouchaoui, Hind
AU - Gouel, Flore
AU - Rolland, Anne Sophie
AU - Duce, James A.
AU - Devedjian, Jean Christophe
AU - Cassereau, Julien
AU - Bost, Marie
AU - Abrial, Charlotte
AU - Muller, Jeanne
AU - Olivier, Audrey
AU - Le Masson, Gwendal
AU - Mathis, Stéphane
AU - Djigo, Dieynaba
AU - Bonabaud, Sarah
AU - Deloire, Mathilde
AU - Genestet, Steeve
AU - Menanteau, Elsa
AU - Bourgeois, Pauline
AU - Lefilliatre, Mathilde
AU - Viader, Fausto
AU - Abrou, Mouloud
AU - Chavanne, Damien
AU - Bari, Rachida
AU - Guy, Nathalie
AU - Arondo, Sophia Sickout
AU - Rouvet, Sandrine
AU - Beauvais, Katell
AU - Aidan, Mathilde
AU - Madec, Olivier
AU - Danel-Brunaud, Veronique
AU - Tard, Celine
AU - Pleuvret, Marie
AU - Santraine, Valerie
AU - Moutarde, Julie
AU - Couratier, Philippe
AU - Lautrette, Géraldine
AU - Machat, Selma
AU - Penoty, Marie
AU - Villeneuve, Olivier
AU - Labetoulle, Clémence
AU - Catteau, Julie
AU - Bernard, Emilien
AU - Svahn, Juliette
AU - Neuillet, Camille
AU - Attarian, Shahram
N1 - Publisher Copyright:
© 2020, Springer-Verlag GmbH Austria, part of Springer Nature.
PY - 2020/2/1
Y1 - 2020/2/1
N2 - Focal iron accumulation associated with brain iron dyshomeostasis is a pathological hallmark of various neurodegenerative diseases (NDD). The application of iron-sensitive sequences in magnetic resonance imaging has provided a useful tool to identify the underlying NDD pathology. In the three major NDD, degeneration occurs in central nervous system (CNS) regions associated with memory (Alzheimer’s disease, AD), automaticity (Parkinson’s disease, PD) and motor function (amyotrophic lateral sclerosis, ALS), all of which require a high oxygen demand for harnessing neuronal energy. In PD, a progressive degeneration of the substantia nigra pars compacta (SNc) is associated with the appearance of siderotic foci, largely caused by increased labile iron levels resulting from an imbalance between cell iron import, storage and export. At a molecular level, α-synuclein regulates dopamine and iron transport with PD-associated mutations in this protein causing functional disruption to these processes. Equally, in ALS, an early iron accumulation is present in neurons of the cortico-spinal motor pathway before neuropathology and secondary iron accumulation in microglia. High serum ferritin is an indicator of poor prognosis in ALS and the application of iron-sensitive sequences in magnetic resonance imaging has become a useful tool in identifying pathology. The molecular pathways that cascade down from such dyshomeostasis still remain to be fully elucidated but strong inroads have been made in recent years. Far from being a simple cause or consequence, it has recently been discovered that these alterations can trigger susceptibility to an iron-dependent cell-death pathway with unique lipoperoxidation signatures called ferroptosis. In turn, this has now provided insight into some key modulators of this cell-death pathway that could be therapeutic targets for the NDD. Interestingly, iron accumulation and ferroptosis are highly sensitive to iron chelation. However, whilst chelators that strongly scavenge intracellular iron protect against oxidative neuronal damage in mammalian models and are proven to be effective in treating systemic siderosis, these compounds are not clinically suitable due to the high risk of developing iatrogenic iron depletion and ensuing anaemia. Instead, a moderate iron chelation modality that conserves systemic iron offers a novel therapeutic strategy for neuroprotection. As demonstrated with the prototype chelator deferiprone, iron can be scavenged from labile iron complexes in the brain and transferred (conservatively) either to higher affinity acceptors in cells or extracellular transferrin. Promising preclinical and clinical proof of concept trials has led to several current large randomized clinical trials that aim to demonstrate the efficacy and safety of conservative iron chelation for NDD, notably in a long-term treatment regimen.
AB - Focal iron accumulation associated with brain iron dyshomeostasis is a pathological hallmark of various neurodegenerative diseases (NDD). The application of iron-sensitive sequences in magnetic resonance imaging has provided a useful tool to identify the underlying NDD pathology. In the three major NDD, degeneration occurs in central nervous system (CNS) regions associated with memory (Alzheimer’s disease, AD), automaticity (Parkinson’s disease, PD) and motor function (amyotrophic lateral sclerosis, ALS), all of which require a high oxygen demand for harnessing neuronal energy. In PD, a progressive degeneration of the substantia nigra pars compacta (SNc) is associated with the appearance of siderotic foci, largely caused by increased labile iron levels resulting from an imbalance between cell iron import, storage and export. At a molecular level, α-synuclein regulates dopamine and iron transport with PD-associated mutations in this protein causing functional disruption to these processes. Equally, in ALS, an early iron accumulation is present in neurons of the cortico-spinal motor pathway before neuropathology and secondary iron accumulation in microglia. High serum ferritin is an indicator of poor prognosis in ALS and the application of iron-sensitive sequences in magnetic resonance imaging has become a useful tool in identifying pathology. The molecular pathways that cascade down from such dyshomeostasis still remain to be fully elucidated but strong inroads have been made in recent years. Far from being a simple cause or consequence, it has recently been discovered that these alterations can trigger susceptibility to an iron-dependent cell-death pathway with unique lipoperoxidation signatures called ferroptosis. In turn, this has now provided insight into some key modulators of this cell-death pathway that could be therapeutic targets for the NDD. Interestingly, iron accumulation and ferroptosis are highly sensitive to iron chelation. However, whilst chelators that strongly scavenge intracellular iron protect against oxidative neuronal damage in mammalian models and are proven to be effective in treating systemic siderosis, these compounds are not clinically suitable due to the high risk of developing iatrogenic iron depletion and ensuing anaemia. Instead, a moderate iron chelation modality that conserves systemic iron offers a novel therapeutic strategy for neuroprotection. As demonstrated with the prototype chelator deferiprone, iron can be scavenged from labile iron complexes in the brain and transferred (conservatively) either to higher affinity acceptors in cells or extracellular transferrin. Promising preclinical and clinical proof of concept trials has led to several current large randomized clinical trials that aim to demonstrate the efficacy and safety of conservative iron chelation for NDD, notably in a long-term treatment regimen.
KW - Amyotrophic lateral sclerosis
KW - Conservative iron chelation
KW - Ferroptosis
KW - Iron metabolism
KW - Parkinson’s disease
UR - http://www.scopus.com/inward/record.url?scp=85077575116&partnerID=8YFLogxK
U2 - 10.1007/s00702-019-02138-1
DO - 10.1007/s00702-019-02138-1
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C2 - 31912279
AN - SCOPUS:85077575116
SN - 0300-9564
VL - 127
SP - 189
EP - 203
JO - Journal of Neural Transmission
JF - Journal of Neural Transmission
IS - 2
ER -