Pridopidine’s Mechanism of Action Suggests Neuroprotective Effects in Huntington Disease

The effect pridopidine had on reducing mutant HTT-induced endoplasmic reticulum stress via the activation of sigma-1 receptor provided additional evidence of its therapeutic potential.

A trio of recently published peer-reviewed journal articles have provided insights into pridopidine’s (Prilenia Therapeutics) neuroprotective properties through activation of the sigma-1 receptor (S1P) in neurodegenerative diseases.1-4

Pridopidine, a first-in-class small molecule currently in development for the treatment of Huntington disease (HD) and amyotrophic lateral sclerosis (ALS), showed an ability to enhance mitochondrial function and reduce mutant human huntingtin (mHTT)-induced stressed, which are impaired in HD and are mediated by the S1R. “These new insights on pridopidine and how it affects S1R continue to advance our knowledge on its mechanism of action, which supports the development of this drug for HD and ALS,” Michael R. Hayden, MD, PhD, chief executive officer, Prilenia, said in a statement.1

The first study investigated the protective effects of pridopidine on various mitochondrial dynamics in primary neurons from YAC128 HD mice expressing the mHTT gene.2 Results showed that the therapy prevented the disruption of mitochondria-endoplasmic reticulum (ER) contact sites and improved the colocalization of inositol 1,4,5-trisphosphate receptor (IP3R) and its chaperone S1R, leading to increased mitochondrial activity, elongation, and motility.

YAC128 mice treated at early or presymptomatic age with pridopidine showed significant improvement in motor coordination, which the investigators noted indicated a delay in symptom onset. The treatment also reduced mitochondrial reactive oxygen species (ROS) levels by normalizing mitochondrial complex activity.

Results from the second published analysis showed that pridopidine significantly ameliorates mHTT-induced ER stress in cellular HD models, starting at low nanomolar concentrations.3 The levels of 3 branches of the unfolded protein response (UPR) also were reduced, with the strongest effects seen on the PKR-like endoplasmic reticulum kinase (PERK) branch. Those data also showed that the treatment enhanced the levels of insoluble S1R, suggesting the stabilization of activated S1R oligomers. Notably, these S1R oligomeric species appeared in ER-localized patches, and not in the mitochondria-associated membranes nor the ER-derived quality control compartment.

The final publication investigated S1R’s interaction with cholesterol, and whether it enables the formulation of cholesterol-enriched microdomains in the ER membrane.4 Investigators first hypothesized that a number of secreted and signaling proteins are recruited and retained in these microdomains.

Results of an unbiased screening for S1R-interaction partners, performed using the engineered ascorbate peroxidase 2 technology, was consistent with the aforementioned hypothesis. Additionally, investigators also proposed that S1R agonists enable the disassembly of these cholesterol-enriched microdomains and the release of accumulated proteins such as ion channels, signaling receptors, and trophic factors from the ER. Lead author Vladimir Zhemkov, PhD, postdoctoral researcher, UT Southwestern Medical Center, and colleagues concluded that "this hypothesis may explain the pleotropic signaling functions of the S1R, consistent with previously observed effects of S1R agonists in various experimental systems.”

Pridopidine is currently also being assessed in the phase 3 PROOF-HD study, which evaluates the safety and efficacy of the drug in 45-mg doses on Total Functional Capacity in patients with early-stage HD.1 Additionally, the recently completed PRIDE-HD study also showed a maintenance of functional capacity with the treatment compared to placebo in patients with early-stage HD.

REFERENCES
1. New research supports pridopidine’s neuroprotective properties in Huntington disease models. News release. May 25, 2021. Accessed July 6, 2021. https://www.prilenia.com/pridopidines-neuroprotective-properties-in-huntingtons-disease
2. Naia L, Ly P, Mota SI, et al. The sigma-1 receptor mediates pridopidine rescue of mitochondrial function in Huntington disease models. Neurotherapeutics. Published online April 1, 2021. doi: 10.1007/s13311-021-01022-9
3. Shenkman M, Geva M, Gershoni-Emek N, Hayden MR, Lederkremer GZ. Pridopidine reduces mutant huntingtin-induced endoplasmic reticulum stress by modulation of the sigma-1 receptor. J Neurochem. Published online April 19, 2021. doi: 10.1111/jnc.15366
4. Zhemkov V, Geva M, Hayden MR, Bezprozvanny I. Sigma-1 receptor (S1R) interaction with cholesterol: mechanisms of S1R activation and its role in neurodegenerative diseases. Int J Mol Sci. Published online April 15, 2021. doi: 10.3390/ijms22084082