Anti-prion drugs reduce endoplasmic reticulum stress and protect human dopaminergic neurons from death
Year: 2025
Type: article
Abstract: 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.
Source: Biomedicine & Pharmacotherapy
Institutions: Inserm, Université de Bretagne Occidentale, Génétique, Génomique Fonctionnelle et Biotechnologies, Laboratoire de Traitement de l'Information Médicale, Université de Bretagne Occidentale, Royal Holloway University of London, Sorbonne Université, Institut de Myologie, Centre de Recherche en Myologie, University of Konstanz, Centre National de la Recherche Scientifique, Laboratoire d'Innovation Thérapeutique, Université de Strasbourg
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,610
Funders: Institut de France, University of Cambridge, Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, Université de Strasbourg, Ministère de l'Education Nationale, de l'Enseignement Superieur et de la Recherche, Centre National de la Recherche Scientifique, AFM-Téléthon, Université de Bretagne Occidentale, Ministère de l'Enseignement supérieur, de la Recherche et de l'Innovation, Région Bretagne, Sorbonne Université, Société d'Accélération du Transfert de Technologies, Royal Holloway, University of London, Association Gaétan Saleün, Institut de Myologie
OpenAlex ID: W4416448901