ALDH4A1 expression levels are elevated in postmortem brains of patients with schizophrenia and are associated with genetic variants in enzymes related to proline metabolism

Background: The molecular mechanisms underlying schizophrenia remain largely unclear, and we recently identified multiple proteins significantly altered in the postmortem prefrontal cortex (PFC) of schizophrenia patients amongst which aldehyde dehydrogenase 4 family member A1 (ALDH4A1) was especially elevated. In this study, we aimed to investigate the expression of ALDH4A1 in the PFC and superior temporal gyrus (STG) and to elucidate functional correlations between schizophrenia risk alleles and molecular expression profiles in the postmortem brains of patients with schizophrenia. Methods: The levels of ALDH4A1 protein expression in the PFC and STG in postmortem brains from 24 patients with schizophrenia, 8 patients with bipolar disorder, and 32 controls were assessed using enzyme-linked immunosorbent assay. Moreover, we explored the associations between ALDH4A1 expression and genetic variants in enzymes associated with proline metabolism, including ALDH4A1 (schizophrenia [n = 22], bipolar disorder [n = 6], controls [n = 11]). Results: ALDH4A1 levels were significantly elevated in both the PFC and STG in patients with schizophrenia and tended to elevate in patients with bipolar disorder. Furthermore, ALDH4A1 expression levels in the PFC were significantly associated with the following three single-nucleotide polymorphisms: rs10882639, rs33823, rs153508. We also found partial coexpression of ALDH4A1 in mitochondria in a subset of putative astrocytes of postmortem brain. Limitations: Our study population was relatively small, particularly for a genetic study. Conclusion: These findings indicate that altered expression of ALDH4A1 may reflect the potential molecular mechanisms underlying the pathogenesis of schizophrenia and bipolar disorder, and may aid in the development of novel drug therapies.