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The Postmortem Human Brain to Characterize Novel Drug Targets for Psychiatric Disorders: Using FKBP5 as an Example

Journal Article


Abstract


  • Background

    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.

    Methods

    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.

    Results

    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.

    Conclusions

    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.

Authors


  •   Matosin, Natalie
  •   Martinelli, Silvia (external author)
  •   Cruceanu, Cristiana (external author)
  •   Turecki, Gustavo (external author)
  •   Binder, Elisabeth B. (external author)

Publication Date


  • 2018

Citation


  • Matosin, N., Martinelli, S., Cruceanu, C., Turecki, G. & Binder, E. (2018). The Postmortem Human Brain to Characterize Novel Drug Targets for Psychiatric Disorders: Using FKBP5 as an Example. Biological Psychiatry, 83 (9), S28-S29.

Start Page


  • S28

End Page


  • S29

Volume


  • 83

Issue


  • 9

Place Of Publication


  • United States

Abstract


  • Background

    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.

    Methods

    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.

    Results

    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.

    Conclusions

    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.

Authors


  •   Matosin, Natalie
  •   Martinelli, Silvia (external author)
  •   Cruceanu, Cristiana (external author)
  •   Turecki, Gustavo (external author)
  •   Binder, Elisabeth B. (external author)

Publication Date


  • 2018

Citation


  • Matosin, N., Martinelli, S., Cruceanu, C., Turecki, G. & Binder, E. (2018). The Postmortem Human Brain to Characterize Novel Drug Targets for Psychiatric Disorders: Using FKBP5 as an Example. Biological Psychiatry, 83 (9), S28-S29.

Start Page


  • S28

End Page


  • S29

Volume


  • 83

Issue


  • 9

Place Of Publication


  • United States