Cortical PGC-1α-Dependent Transcripts Are Reduced in Postmortem Tissue From Patients With Schizophrenia

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α) is implicated in neurological disorders.
• PGC-1α regulates critical cortical genes involved in neuronal function.

Purpose of the Study:

• To investigate the role of PGC-1α and its associated transcriptional programs in schizophrenia pathophysiology.
• To examine the expression of PGC-1α-dependent genes in postmortem brain tissue from schizophrenia patients.

Main Methods:

• Measured mRNA expression of PGC-1α and target genes (PV, Syt2, Cplx1, Nefh) in human cortical tissue.
• Analyzed promoter regions for transcription factor binding sites.
• Assessed the relationship between PGC-1α, NRF-1, and target gene expression.

Main Results:

• Reduced expression of PGC-1α-dependent transcripts in schizophrenia patients, despite unchanged PGC-1α levels.
• Nuclear respiratory factor 1 (NRF-1) mRNA expression was reduced in schizophrenia and predicted target gene levels.
• The correlation between PGC-1α and target genes was lost in schizophrenia patients with low NRF-1.

Conclusions:

• Schizophrenia involves disrupted PGC-1α and/or NRF-1 transcriptional programs in the cortex.
• NRF-1 is critical for PGC-1α target gene expression in schizophrenia.
• Enhancing PGC-1α or NRF-1 activity may restore cortical function.