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Validating PD targets: FK506 binding proteins

Mark Frasier, PhD, Associate Director, Research Programs, Michael J. Fox Foundation for Parkinson's Research (MJFF)
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POWs: February 16-22, 2010
Papers of the Week
PDOR Administrator, The Michael J. Fox Foundation for Parkinson's Research
22 Feb 2010 04:34 PM EST
1: Na SJ, Dilella AG, Lis EV, Jones K, Levine DM, Stone DJ, Hess JF. MolecularProfiling of a 6-Hydroxydopamine Model of Parkinson's Disease. Neurochem Res. ... 
Responses: 2

Digging through the POWs, I found this interesting paper from Veerle Baekelandt's group describing the role of FK506 binding proteins (FKBPs) in alpha-synuclein accumulation and alpha-synuclein mediated cell death. The group elegantly dissects the role of several FKBPs in alpha-synuclein accumulation in cell culture models by either specifically reducing levels by shRNA or over-expressing different FKBPs. The group observed FKBP12 seems to have the most prominent effect in accelerating asyn accumulation; this effect is attenuated by the addition of FK506.

The investigators go on to examine whether FK506 reduces alpha-synuclein accumulation in vivo using a lentiviral mediated delivery of alpha-synuclein to the striatum of mice. They observed that chronic treatment (5 months) of mice with FK506 reduced alpha-synuclein accumulation and seem to increase the survival of alpha-synuclein cells. Interestingly, the group did not observe any dose response after testing 3 different doses of FK506 in the viral synuclein model but rather observed an effect in the lowest dose that matched the effect observed the two higher doses.

This paper supports the validation of FKBPs as potential targets for PD therapy and calls for additional work examining selective and specific inhibitors of the various FKBP isoforms in PD models. Several questions emerge in terms of "next steps":

1. FK506--what concentration of FK506 reaches the striatum upon oral administration in this study? The authors state the drug crosses the blood brain barrier--is it known what at what levels using this dosing paradigm?

2. Models of alpha-synuclein over-expression--FKBP appears to accelerate accumulation and aggregation of alpha-synuclein; is this specific to alpha-synuclein? Are other proteins such as tau affected by FKBP in this manner?

3. Petidyl-prolyl-isomerases: Should one look at other enzymes in this class as potential targets? Pin1, for example, may be a similarly attractive target for alpha-synuclein mediated toxicity (Rudrabhatla et. al 2010)

 

Reference: 
Gerard M, Deleersnijder A, Daniëls V, Schreurs S, Munck S, Reumers V, et al. Inhibition of FK506 Binding Proteins Reduces {alpha}-Synuclein Aggregation and Parkinson's Disease-Like Pathology. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2010;30(7):2454-63.
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Rudrabhatla P, Pant HC. Phosphorylation-specific peptidyl-prolyl isomerization of neuronal cytoskeletal proteins by Pin1: implications for therapeutics in neurodegeneration. J Alzheimers Dis. 2010;19(2):389-403.
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