This paper below tells more closely than the Finkelstein paper (the only PBT434 paper) how ferroptosis happens in the same Parkinson's disease model used in the PBT434 paper. It does not talk about alpha-synuclein but it tells about how the balance between Fe2+ and Fe3+ is controlled and how that relates to ROS production. This latter thing was also monitored in the Finkelstein paper. It demonstrated clearly that PBT434 reduced ROS production ( 8-isoprostane content measure). and demonstrated correspondingly that there was clearly less cell death (ferroptosis) in PBT434 treated animals as this new paper suggests to happen if that is the case. So most likely mitochondrial membrane potential did not go down so much in the PBT434 treated animals. That is however an issue we do not yet know but perhaps in the next 434 paper.

Int J Mol Med

. 2021 Apr;47(4):61.

doi: 10.3892/ijmm.2021.4894. Epub 2021 Mar 2.

miR‑335 promotes ferroptosis by targeting ferritin heavy chain 1 in in vivo and in vitro models of Parkinson's disease

Xinrong Li ¹, Wenwen Si ¹, Zhan Li ², Ye Tian ³, Xuelei Liu ⁴, Shanyu Ye ⁵, Zifeng Huang ¹, Yichun Ji ³, Caiping Zhao ⁴, Xiaoqian Hao ¹, Dongfeng Chen ⁵, Meiling Zhu ¹

Affiliations expand

• PMID: 33649797

DOI: 10.3892/ijmm.2021.4894

Abstract

Parkinson's disease (PD) is a neurodegenerative disease characterized by the selective loss of dopaminergic neurons in the substantia nigra (SN). In a previous study, the authors demonstrated that ferritin heavy chain 1 (FTH1) inhibited ferroptosis in a model of 6‑hydroxydopamine (6‑OHDA)‑induced PD. However, whether and how microRNAs (miRNAs/miRs) modulate FTH1 in PD ferroptosis is not yet well understood. In the present study, in vivo and in vitro models of PD induced by 6‑OHDA were established. The results in vivo and in vitro revealed that the levels of the ferroptosis marker protein, glutathione peroxidase 4 (GPX4), and the PD marker protein, tyrosine hydroxylase (TH), were decreased in the model group, associated with a decreased FTH1 expression and the upregulation of miR‑335. In both the in vivo and in vitro models, miR‑335 mimic led to a lower FTH1 expression, exacerbated ferroptosis and an enhanced PD pathology. The luciferase 3'‑untranslated region reporter results identified FTH1 as the direct target of miR‑335. The silencing of FTH1 in 6‑OHDA‑stimulated cells enhanced the effects of miR‑335 on ferroptosis and promoted PD pathology. Mechanistically, miR‑335 enhanced ferroptosis through the degradation of FTH1 to increase iron release, lipid peroxidation and reactive oxygen species (ROS) accumulation, and to decrease mitochondrial membrane potential (MMP). On the whole, the findings of the present study reveal that miR‑335 promotes ferroptosis by targeting FTH1 in in vitro and in vivo models of PD, providing a potential therapeutic target for the treatment of PD.