Targeting endoplasmic reticulum stress and protein misfolding in schizophrenia: the emerging promise of sigma-1 receptor agonists

Schizophrenia is a severe psychiatric disorder marked by significant cognitive, perceptual, and social deficits, the neurobiological basis of which remains incompletely elucidated. Increasing evidence implicates disruptions in protein homeostasis, including misfolding and aggregation of key neuronal proteins, as contributing factors to its pathogenesis. While proteinopathies have been extensively studied in neurodegenerative diseases, their role in schizophrenia has only recently gained attention. Central to these processes is endoplasmic reticulum (ER) stress and the activation of the unfolded protein response, which regulate protein folding and cellular quality control. Dysregulation of ER stress pathways, alongside impaired chaperone protein function and mitochondrial dysfunction, can lead to accumulation of misfolded proteins and neuronal dysfunction. Proteins such as DISC1, CRMP1, NOS1AP, and others have been identified with altered expression and aggregation patterns in schizophrenia, linking protein abnormalities to disease pathology. Additionally, mounting evidence suggests that chronic ER stress can activate microglia, the brain's immune cells, triggering the release of proinflammatory cytokines and promoting neuroinflammation. Sigma-1 receptor, a unique ER chaperone protein involved in modulating ER stress and calcium signaling, has emerged as a critical regulator of neuronal proteostasis and survival. Agonists of the sigma-1 receptor show promising therapeutic potential by alleviating ER stress, enhancing neuroprotection, halting inflammation, and restoring cellular homeostasis in preclinical models of schizophrenia and other brain disorders. In this review, we will discuss these interconnected molecular mechanisms, highlighting novel therapeutic pathways focused on proteostasis restoration and sigma-1 receptor modulation, which offer a promising avenue for future interventions in schizophrenia.