Long-term inhibition of lysosomal glucocerebrosidase activity promotes GPX4 stability and inhibits ferroptosis in dopaminergic neurons.

An increasing number of studies indicate that ferroptosis, a lethal pathway initiated by excessive iron-dependent lipid peroxidation, and pivotal to the survival of dopaminergic neurons and the progression of Parkinson's disease (PD), may be regulated by the lysosomal pathway. Mutation and loss of function of the lysosomal enzyme, glucocerebrosidase, induce the accumulation of glycosphingolipids and alterations in lysosome activity, which have been associated with a higher risk of developing PD. Our present study showed that transient inhibition of glucocerebrosidase activity had a positive effect on lipid peroxidation and ferroptosis. In a dopaminergic cell line (LUHMES cells), it was shown that a 10-day inhibition of glucocerebrosidase activity using conduritol-beta-epoxide (CBE) specifically impeded susceptibility to RSL3-induced ferroptosis, but not to several other inducers of cell death. CBE impaired the lysosomal pathway, modified lipid membrane composition by reducing ether-linked phospholipids in phosphatidylethanolamines, and promoted an increase in glutathione peroxidase 4 (GPX4) protein levels. This phenomenon was transient and disappeared after 20 days of glucocerebrosidase inhibition, suggesting that the cells have the capacity to return to their basal homeostasis. Most of the current compounds acting on GPX4 promote its degradation, thus information on drugs leading to GPX4 stability is key in order to protect neurons against excessive lipid peroxidation occurring in neurodegenerative diseases.