Anti-prion drugs reduce endoplasmic reticulum stress and protect human dopaminergic neurons from death

Parkinson's disease (PD) is characterized by the pathologic aggregation of α-synuclein, which induces endoplasmic reticulum (ER) stress and activates the unfolded protein response (UPR), ultimately leading to the death of dopaminergic neurons. This study investigated whether drugs known to mitigate protein aggregation in prion disease models would attenuate the stress response and cell death in PD models. Flunarizine and ten of its structural analogues, previously identified through a drug repositioning approach to reduce the aggregation of PrP^Sc prion protein, were evaluated in a Chinese hamster ovary (CHO-K1) cell model. First, UPR was induced in CHO-K1 cells using tunicamycin, revealing that several of these drugs conferred protection and also reduced the expression of the UPR marker CHOP. Subsequently, we tested these anti-prion drugs in PD relevant cellular models. Neuronally-differentiated PC12 cells were employed, and all 11 drugs exhibited protective effect. Finally, human dopaminergic neurons (LUHMES cells) were exposed to 1-methyl-4-phenylpyridinium (MPP+), a compound commonly used to induce parkinsonian-like pathology. In this model, all 11 drugs demonstrated cytoprotective properties and attenuated UPR. Notably, several compounds - benzydamine, duloxetine, flunarizine, metixene and triflupromazine - protected LUHMES cells from MPP+ -induced ER stress at nanomolar concentrations. These findings provide the proof of concept that drugs selected for other indications, may be repurposed to ameliorate PD and related pathologies linked to ER stress.