Iron and PD and neuron loss

Ferroptosis, a newly characterized form of cell death in Parkinson's disease that is regulated by PKC

Bruce Do Van et al.

Highlights

•This study is the first to emphasize the role of ferroptosis in Parkinson’ Disease.
•Ferroptosis was characterized in LUHMES cells, ex vivo and in vivo.
•Some of the observed characteristics of ferroptosis differed from those reported previously.
•Ferroptosis may be initiated by PKCalpha activation, in a RAS-independent manner.
•Iron chelators, Fer-1 and PKC inhibitors may prevent neuron loss in Parkinsonians.

Abstract


Parkinson's disease (PD) is a complex illness characterized by progressive dopaminergic neuronal loss. Several mechanisms associated with the iron-induced death of dopaminergic cells have been described. Ferroptosis is an iron-dependent, regulated cell death process that was recently described in cancer. Our present work show that ferroptosis is an important cell death pathway for dopaminergic neurons. Ferroptosis was characterized in Lund human mesencephalic cells and then confirmed ex vivo (in organotypic slice cultures) and in vivo (in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model). Some of the observed characteristics of ferroptosis differed from those reported previously. For example, ferroptosis may be initiated by PKCα activation, which then activates MEK in a RAS-independent manner. The present study is the first to emphasize the importance of ferroptosis dysregulation in PD. In neurodegenerative diseases like PD, iron chelators, Fer-1 derivatives and PKC inhibitors may be strong drug candidates to pharmacologically modulate the ferroptotic signaling cascade.