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

Chiara Milanese, Sylvia Gabriels, Sander Barnhoorn, Silvia Cerri, Ayse Ulusoy, S. V. Gornati, Daniel F. Wallace, Fabio Blandini, Donato A. Di Monte, V. Nathan Subramaniam, Pier G. Mastroberardino*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

3 Citations (Scopus)
2 Downloads (Pure)

Abstract

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.

Original languageEnglish
Pages (from-to)1720-1732
Number of pages13
JournalCell Death and Differentiation
Volume28
Issue number5
Early online date16 Dec 2020
DOIs
Publication statusPublished - May 2021

Bibliographical note

Funding Information:
Acknowledgements This work was supported by a Target Advancement grant from the Michael J. Fox Foundation for Parkinson’s Research (PGM).

Publisher Copyright:
© 2020, The Author(s).

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