Disruptions to the levels or functions of molecules in psychopathology form the rationale for their use as drug targets. However, changes in target molecules and their bioavailability can influence drug efficiency in patients. Characterizing alterations of key molecules directly in the brain can help develop appropriate pharmacological strategies. FKBP5 is a novel cross-disorder drug target for psychiatric conditions. In-depth characterization of brain-expressed FKBP5 is required to transition FKBP5-targeting drugs into the clinic.
RNA sequencing was performed in postmortem samples from the anterior cingulate cortex (ACC) and hippocampus (HIP) of 13 bipolar disorder (BPD) and 13 controls with the Illumina HiSeq2000 platform. Reads were aligned and gene/isoform-level counts were derived. Immunohistochemistry analysis (IHC) of FKBP5 expression was also performed.
A truncated transcript of FKBP5 (variant 4) was increased in BPD vs controls (ACC -66.39%; HIP +35.76%). In the ACC, variant 1 was also increased in BPD (+70.33%), while variant 2 was decreased (-36.81%). These alterations were not seen in HIP. IHC indicated that total FKBP5 expression might be limited to neurons, with co-localized staining of FKBP5 with neuronal marker NeuN, but not GFAP.
These data indicate that FKBP5 is altered in BPD in a transcript-specific manner. Notably a variant 4, encoding a truncated FKBP5 protein, was increased in BPD in both the ACC and HIP. This truncated FKBP5 protein likely has unique functionality, thus alterations in this protein might have implications for therapeutic efforts targeted at FKBP5. Further analyses are now being conducted to determine the functional significance of variant 4.