Overcoming Neurodegenerative Diseases Through Autophagy Initiation by Pridopidine

This study reveals the signaling pathway underlying how pridopidine acts as an agonist in promoting autophagy for neuron protection. When a motor neuron is under pathological threats, pridopidine dissociates chaperone protein SIGMAR1 from HSPA5, allowing SIGMAR1 to proceed to the nuclear pore to chaperone nucleoporin POM121. Then, POM121 recruits KPNB1 so as to create an effective in-bound transportation of TFEB (from cytosol into nucleus), which is crucial for the initiation of autophagy. For the first time, the impact of SIGMAR1 agonists and antagonists on the chaperone activity of SIGMAR1 is elucidated, proving that the SIGMAR1 is a ligand-regulated chaperone. Results indicate that, with the presence of chaperone, the structural nucleoporin POM121 also serves as a signaling molecule which enables TFEB-mediated autophagy. Notably, pridopidine is able to effectively protect motor neuron NSC34 against H2O2-induced toxicity expressing the pathogenic (G4C2)288 repeat. In the absence of pridopidine in transfected NSC34 motor neuron, hexanucleotide (G4C2)RNA expansion (HRE) disrupts TFEB transport by hindering the interaction between SIGMAR1 and POM121. By complementing these discoveries with the ongoing clinical development of pridopidine, future studies may focus on designing a higher-efficacy therapy to treat neurodegenerative diseases.

Neurodegenerative diseases, such as Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS), are closely related to impairments in autophagy. In ALS-frontotemporal lobar degeneration (ALS-FTD), autophagy is disrupted due to the defective transportation of transcription factor TFEB from the cytosol into the nucleus. Hexanucleotide (G4C2)RNA expansion (HRE) is accountable for the impairment but the exact molecular pathway involved has not been reported yet. Meanwhile, although the chaperone protein SIGMAR1 plays a pivotal role in autophagy, the underlying mechanism was ambiguous. Thus, this research aims to answer these uncertainties and also to examine the mechanism underlying the neuroprotective effect of pridopidine. The study outcome indicates that, by targeting the SIGMAR1, a pharmacological approach could potentially be designed to overcome diseases related to autophagy impairment.

Millions of people suffer from neurodegenerative diseases globally. In United States, approximately 6 million and 1 million people are reported to be the victims of Alzheimer’s disease and Parkinson’s disease, respectively. These alarming figures can possibly be reduced by therapies which target the chaperone protein SIGMAR1. By explaining how pridopidine activates SIGMAR1, this research paves a clear direction which facilitates the development of therapies to treat neurodegenerative diseases (UNSDG 3: Good Health & Well-Being).