Gender biased neuroprotective effect of Transferrin Receptor 2 deletion in multiple models of Parkinson’s disease
| Autor: | Simona V. Gornati, Ayse Ulusoy, Donato A. Di Monte, Chiara Milanese, Daniel F. Wallace, Pier Giorgio Mastroberardino, Sander Barnhoorn, Fabio Blandini, Silvia Cerri, V. Nathan Subramaniam, Sylvia Gabriels |
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| Přispěvatelé: | Molecular Genetics, Neurosciences |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Parkinson's disease
Substantia nigra Transferrin receptor Biology Neuroprotection Article Mice genetics [Parkinson Disease] Receptors Transferrin medicine Neurotoxin Animals Humans ddc:610 Molecular Biology chemistry.chemical_classification Pars compacta pharmacology [Neuroprotective Agents] Dopaminergic Gender Identity Parkinson Disease Cell Biology medicine.disease therapeutic use [Neuroprotective Agents] Ageing Disease Models Animal Neuroprotective Agents chemistry nervous system Transferrin Metals Female metabolism [Receptors Transferrin] Neuroscience Neurological disorders |
| Zdroj: | Cell death and differentiation 28(5), 1720-1732 (2021). doi:10.1038/s41418-020-00698-4 Cell Death and Differentiation Cell Death and Differentiation, 28(5), 1720-1732. Nature Publishing Group |
| ISSN: | 1350-9047 |
| DOI: | 10.1038/s41418-020-00698-4 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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