Region-specific dysregulation of proline metabolic enzymes underlying mitochondrial dysfunction in the postmortem brains of patients with schizophrenia

This is the authors' abstract. We don't add key points for this paper.

Proline metabolism has been associated with schizophrenia pathophysiology; however, the underlying molecular mechanisms remain elusive. This study aimed to investigate the changes in the entire proline metabolic pathway in postmortem brains of patients with schizophrenia. Herein, enzyme-linked immunosorbent assay was performed to determine the protein levels of proline metabolism-associated key enzymes (prolidase [PEPD], proline dehydrogenase [PRODH], pyrroline-5-carboxylate synthetase [ALDH18A1], ornithine aminotransferase [OAT], and pyrroline-5-carboxylate reductase 1 [PYCR1]). Additionally, amino acids metabolized through the proline pathway, including proline, ornithine, and glutamic acid, were quantitatively analyzed through liquid chromatography-tandem mass spectrometry. The alterations in the expression of proline metabolism-associated enzymes and associated amino acid levels were analyzed in the postmortem brains of individuals with schizophrenia, and their associations with premortem clinical symptom scores were examined. Notably, in patients with schizophrenia, PRODH and PYCR1 expression significantly decreased in the superior temporal gyrus and prefrontal cortex, respectively, whereas amino acid levels showed no significant differences. Overall, the findings of this study show that dysregulation in proline metabolism may contribute to mitochondrial dysfunction owing to its close association with energy production and redox regulation. These results suggest the underlying pathophysiology of schizophrenia and provide insights for developing novel therapeutic strategies for managing schizophrenia.