br Role of ferroptosis in PD Pathological progression of PD

Role of ferroptosis in PD Pathological progression of PD displays features that may facilitate ferroptosis induction such as elevated iron in the SNpc [49], [57], [88], [122], depleted GSH [194] and lipid peroxidation [51]. Iron chelation has been shown to mitigate the motor impairment in mouse models of PD [8], [120], [122], and in a human clinical trial [48]. Further iron chelation was found to enhance GPX activity in the CSF [48]. Similarly, N-acetylcysteine (NAC), an antioxidant that can enhance Caffeine australia GSH, offers partial protection against neurodegeneration in PD mouse models [36], [159], [164]. Further, a recent short term (3 months) phase II clinical trial (NCT02445651) indicated protection of dopaminergic neurons in the caudate and putamen in PD patients receiving NAC with concomitant significant improvement in clinical symptoms [145]. A recent study characterised erastin-induced ferroptosis in a cell culture model of PD [Lund human mesencephalic cells (LUHMES)] and ex vivo using organotypic slice cultures. Further, the study showed that the ferroptosis inhibitor, ferrostatin-1, can prevent neuron loss and behavioural impairment in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse PD model [57]. Further, cell death initiated in LUHMES cells using environmental neurotoxins such as rotenone and paraquat, that are causally associated to sporadic PD, was rescued by the iron chelator deferiprone, ferrostatin-1 and liproxstatin-1 [57]. Taken together, these studies indicate that ferroptosis inhibitors may be effective in PD.
Ferroptosis in other neurological conditions Cell death mechanisms associated with neurological impairment remain poorly understood. However, conditions that may favour ferroptosis, such as elevated brain iron and diminished GSH, conspicuously appear across multiple neurodegenerative and certain psychiatric disorders [15], [44], [71], [81], [134], [190].
Conclusion and future perspectives AD and PD continue to be major health challenges with the situation set to worsen as global populations continue to age. With little to no progress in treatment modalities new hypothesis are required to treat, if not explain, neurodegenerative process associated with these debilitating conditions. Iron dysregulation in the brain implicated in these and several other neurodegenerative disorders coupled with deeper understanding of iron-mediated/dependent cell death pathways, such as ferroptosis, may offer interesting and new therapeutic avenues. While anti-ferroptotic molecules show remarkable potency in vitro their clinical use is limited due to their inability to cross the BBB. Thus, there is a potential to develop the next class of molecules that may breach this barrier. Possible strategies may include conjugating anti-ferroptotic molecules to BBB-permeable peptides or packaging anti-ferroptotic agents within nanoparticles or liposomes that allow for specific uptake across the BBB [17], [73], [107], [128]. Iron chelators that can cross the BBB are under investigation in clinical settings now. Anti-ferroptotic therapies based on iron chelation may be advantageous as they may mitigate a broad range of neurodegenerative processes. In the future a better understanding of the effector arm of ferroptosis may offer a range of theranostic opportunities.
Acknowledgements The authors would like to thank Dr. Abdel Ali Belaidi, Dr. Scott Ayton and Dr. Darius Lane (Melbourne Dementia Research Centre, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Australia) for their valuable feedback on the drafts of this manuscript. AIB is supported by funds from the National Health & Medical Research Council of Australia (GNT1103703, GNT1101533). AIB is a shareholder in Prana Biotechnology Ltd, Cogstate Ltd., Brighton Biotech LLC, Grunbiotics Pty Ltd, Eucalyptus Pty Ltd., and Mesoblast Ltd. He is a paid consultant for, and has a profit share interest in, Collaborative Medicinal Development Pty Ltd. CM has received grants from the France Parkinson charity. DD has received PHRC grants from the French Ministry of Health and research funding from the ARSLA charity, France Parkinson charity, Credit Agricole Foundation, and Horizon 2020 (Grant No. 633190) from the European Commision. He has led two pilot investigator driven studies with DFP provided for free by ApoPharma [FAIRPARK-I (NCT00943748) and SAFE-FAIR ALS-I (NCT02164253)]. He is leading two large investigator driven studies with DFP provided for free by ApoPharma [FAIRPARK-II (NCT02655315) and FAIR ALS-II (NCT03293069)]. He served on advisory boards, served as a consultant and given lectures for pharmaceutical companies such as Orkyn, Abbvie, Boston Scientific.