Neuroimmunology and Therapeutics

Biography

Biography: Gabriela Caraveo

Abstract

Calcineurin is a highly conserved Ca2+ calmodulin-dependent phosphatase that plays a key role in sensing Ca2+ concentrations and transducing that information into cellular responses. α-Synuclein (α-syn) is a small lipid binding protein whose misfolding and accumulation in Lewy Bodies is a pathological hallmark of several neurodegenerative diseases collectively known as synucleinopathies for which Parkinson’s Disease (PD) is the most prevalent. We previously showed that α-syn overexpression leads to high rises in cytosolic Ca2+ leading to an over-activation of calcineurin which dephosphorylates a subset of substrates that result in toxicity. Decreasing, but not eliminating calcineurin activity with compounds such as FK506 shift s the spectrum of substrates and results in protection. FK506 impairs calcineurin function by locking it into a complex with the immunophilin FKBP12. Through an integrated genetic and unbiased whole shotgun proteomic approach we now establish the importance of FKBP12 in modulating α-syn toxicity in both calcineurin-dependent an independent manner. Moreover, we demonstrate the efficacy of FK506 in vivo using a rat model for PD. FK506 has the ability to cross the blood brain barrier and is an FDA approved drug typically used as an immunosupressant in the clinic. Since our findings establish the importance of modulating FKBP12 activities at sub-immunosupressive doses to achieve neuroprotection, FK506 could immediately translate into the clinic to treat patients with synucelinopathies such as PD.