Sigma Receptor Modulation in Neurodegenerative Disorders

Sigma receptors, comprising two main subtypes (σ1 and σ2), function as ligand-regulated chaperones that localise to endoplasmic reticulum membranes and mitochondrion-associated membranes. Modulation of σ1 receptors influences calcium signalling, lipid trafficking and proteostasis, thereby promoting neuronal survival under conditions of stress. σ2 receptors, recently identified as TMEM97, participate in lipid homeostasis and cellular stress responses. Dysregulation of sigma receptors has been implicated in the pathogenesis of Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease and ischemic stroke. Agonists at σ1 receptors enhance mitochondrial bioenergetics, reduce endoplasmic reticulum stress and attenuate excitotoxicity, while selective σ2/TMEM97 ligands offer new avenues for imaging and therapeutic intervention. Together, these findings position sigma receptors as versatile targets for disease modification and symptom amelioration across a spectrum of neurodegenerative disorders.

Research from Nature Portfolio

High-resolution crystal structures of the σ1 receptor from Xenopus laevis bound to two endogenous neurosteroids—a putative antagonist (progesterone) and agonist (dehydroepiandrosterone sulfate)—reveal a common binding pocket occupied in opposing orientations. Hydrophobic interactions dominate ligand engagement, with the agonist additionally forming direct hydrogen bonds. Molecular dynamics simulations uncovered a putative water entry pathway that may underlie receptor activation and oligomerisation. These structural insights elucidate the molecular determinants of ligand specificity and pave the way for rational design of sigma-1 receptor modulators with improved neuroprotective profiles.

Sigma Receptor Modulation in Neurodegenerative Disorders publication trend

The graph below shows the total number of articles in sigma receptor modulation in neurodegenerative disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Sigma-1 receptor (σ1 R): A ligand-regulated chaperone protein at the endoplasmic reticulum–mitochondrion interface that modulates calcium signalling, proteostasis and mitochondrial function.

Sigma-2 receptor/TMEM97 (σ2 R): A transmembrane protein involved in lipid homeostasis, endocytic trafficking and stress response, now recognised as a target for imaging and neuroprotective ligands.

Efferocytosis: The phagocytic clearance of apoptotic cells by macrophages and microglia, essential for resolution of inflammation and tissue repair.

Neurosteroid: An endogenous steroid synthesized in the nervous system that modulates receptor activity and neuronal excitability.

Mitochondrion-associated membrane (MAM): A specialised endoplasmic reticulum domain in close contact with mitochondria, critical for calcium exchange, lipid synthesis and cell survival signalling.

References

1. Insight into binding of endogenous neurosteroid ligands to the sigma-1 receptor. Nature Communications (2024).
2. Sigma-1 receptor-regulated efferocytosis by infiltrating circulating macrophages/microglial cells protects against neuronal impairments and promotes functional recovery in cerebral ischemic stroke. Theranostics (2023).
3. Sigma-1 receptor and seizures. Pharmacological Research (2023).
4. Neuronal Sigma-1 Receptors: Signaling Functions and Protective Roles in Neurodegenerative Diseases. Frontiers in Neuroscience (2019).
5. Sigma-1 Receptor Chaperone at the ER-Mitochondrion Interface Mediates the Mitochondrion-ER-Nucleus Signaling for Cellular Survival. PLOS ONE (2013).
6. Sigma-2 Receptor/TMEM97 and PGRMC-1 Increase the Rate of Internalization of LDL by LDL Receptor through the Formation of a Ternary Complex. Scientific Reports (2018).
7. Roles of sigma-1 receptors on mitochondrial functions relevant to neurodegenerative diseases. Journal of Biomedical Science (2017).