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

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.

Insight into Crosstalk between Ferroptosis and Necroptosis: Novel Therapeutics in Ischemic Stroke

“…TFR2 β -KI (lacking TFR2 β mouse model) hearts have showed an increased ferritin heavy chain and a decreased FPN1, while LCKO-KI (selective inactivation of liver TFR2 α in KI mice) hearts have presented an upregulation of ferritin-L chain and DMT1/hepcidin-RNA [ 112 ]. Another central nerve study indicated that TFR2 β deletion exerts neuroprotection against dopaminergic degeneration and against Parkinson's disease- and aging-related iron overload [ 113 ]. However, the efficacy of the regulation of TFR2 β on the CIRI remains unclear; further research should be carried out.…”

Mechanism of miR-132-3p Promoting Neuroinflammation and Dopaminergic Neurodegeneration in Parkinson’s Disease

“…Therefore, a clearer understanding of mechanizing driving PD progression would be beneficial for the proposal of therapeutic approach. A variety of molecular mechanisms that likely contribute to neuronal cell death have been described previously, including α-synuclein aggregation, mitochondrial dysfunction and noxious oxidant stress ( Milanese et al, 2021 ). In addition, neuroinflammation is one of the hallmarks of PD and may induce the degeneration of midbrain dopamine neurons ( Krashia et al, 2019 ).…”

Disulfide bridge-targeted metabolome mining unravels an antiparkinsonian peptide

“…To further enhance its brain targeting property, Aca-LCL was installed with surface-bound transferrin (Tf) to form Tf-Aca-LCL, which was shown to have an improved affinity to the transferrin receptor (TfR) on the surface of nigral dopaminergic neurons ( Fig. 6 B–D) 35 . To address whether Tf-Aca-LCL was BBB-penetrable, a fluorescent agent called IR780 {2-[2-[2-chloro-3-[(1,3-dihydro-3,3-dimethyl-1-propyl- 2H -indol-2-ylidene)ethylidene]-1-cyclohexen-1-yl]ethenyl]-3,3-dimethyl-1-propylindolium iodide} was encapsulated along with acalitide to afford Tf-Aca-LCL-IR780 ( Fig.…”