Pridopidine Protects ALS Patient-Derived Neural Progenitor Cells via Sigma-1 Receptor Activation

Area of Science:

• Neuroscience
• Cell Biology
• Pharmacology

Background:

• Amyotrophic lateral sclerosis (ALS) is characterized by endoplasmic reticulum (ER) stress and mitochondrial dysfunction.
• The sigma-1 receptor (S1R) plays a crucial role in maintaining ER homeostasis and mitochondrial function.
• Disruptions in mitochondria-associated ER membranes (MAMs) are implicated in ALS pathogenesis.

Purpose of the Study:

• To evaluate the neuroprotective effects of pridopidine, a selective S1R agonist, in an in vitro model of sporadic ALS.
• To investigate the impact of S1R activation on ER stress, mitochondrial integrity, and cell survival in patient-derived neural progenitor cells (NPCs).

Main Methods:

• Utilized induced pluripotent stem cell (iPSC)-derived neural progenitor cells (NPCs) from an ALS patient.
• Exposed ALS NPCs to the ER stressor tunicamycin.
• Assessed ER stress markers (BiP, CHOP), mitochondrial membrane potential, apoptosis markers (BAX, caspase-3), and cell viability.
• Investigated the effects of pridopidine and the S1R antagonist NE-100.

Main Results:

• Tunicamycin treatment induced ER stress, mitochondrial dysfunction, apoptosis, and reduced viability in ALS NPCs.
• Pridopidine significantly attenuated tunicamycin-induced ER stress markers in a dose-dependent manner.
• Pridopidine restored mitochondrial membrane potential, reduced apoptosis, and improved ALS NPC survival under ER stress.
• The S1R antagonist NE-100 blocked the protective effects of pridopidine, confirming an S1R-mediated mechanism.

Conclusions:

• S1R activation by pridopidine mitigates ER stress-induced mitochondrial dysfunction and cell death in ALS NPCs.
• Pridopidine demonstrates significant neuroprotective potential by enhancing NPC survival.
• These findings support the therapeutic utility of pridopidine for treating amyotrophic lateral sclerosis.