Modulating FKBP5/FKBP51 and autophagy lowers HTT (huntingtin) levels

Area of Science:

• Neuroscience
• Genetics
• Pharmacology

Background:

• Huntington disease (HD) therapies aim to reduce mutant huntingtin (mHTT).
• Rapamycin, an immunosuppressant, impacts aging and neurological disorders by affecting mTORC1 and cellular clearance.
• The role of FKBP (FK506 binding protein) family members in HD and their therapeutic potential remain unexplored.

Purpose of the Study:

• Investigate alterations in FKBP family members in HD models.
• Determine if FKBP proteins are viable therapeutic targets for Huntington disease.

Main Methods:

• Assessed FKBP5 levels in R6/2 and zQ175 mouse models and human HD neural stem cells.
• Examined FKBP5 interaction and colocalization with huntingtin (HTT) in mouse brain tissues.
• Utilized siRNA and pharmacological inhibitors (SAFit2) to decrease FKBP5 levels/activity.
• Measured mHTT levels, autophagy markers (LC3-II), and autophagic flux.
• Administered SAFit2 in vivo to HD mouse models.

Main Results:

• FKBP5 levels were significantly reduced in HD mouse models and human HD cells.
• FKBP5 was found to interact and colocalize with HTT in the striatum and cortex.
• Decreasing FKBP5 reduced mHTT levels and enhanced autophagic flux in human HD cells.
• Pharmacological inhibition of FKBP5 with SAFit2 reduced mHTT levels independently of mTOR.
• In vivo SAFit2 treatment lowered HTT levels in HD mouse models.

Conclusions:

• FKBP5 is implicated in Huntington disease pathogenesis.
• FKBP5 represents a novel therapeutic target for Huntington disease treatment.
• Targeting FKBP5 offers a potential MTOR-independent strategy for reducing mHTT levels in HD.