Immunophilins and their ligands: insights into survival and growth of human neurons

Avramut, Mihaela; Achim, Cristian L.

doi:10.1016/s0031-9384(02)00934-4

Cited by 35 publications

(39 citation statements)

References 26 publications

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“…Moreover, a higher FKBP12 expression was reported in the brain of PD patients. The protein was also found in Lewy bodies of surviving neurons (Avramut and Achim, 2002). Increased FKBP12 expression may consequently have a profound effect on the regulation of its activity.…”

Section: Discussionmentioning

confidence: 96%

“…Several studies have tried to identify the FKBP member involved and to elucidate the mechanism-of-action (Gold et al, 1997(Gold et al, , 1999 Labrande et al, 2006;Woods et al, 2007). No conclusive answer has been provided so far, but the data suggest that PPIases may play a role in neurodegeneration (Gold et al, 1999;Avramut and Achim, 2002;Edlich et al, 2006;Labrande et al, 2006;Woods et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of FK506 Binding Proteins Reduces α-Synuclein Aggregation and Parkinson's Disease-Like Pathology

Gérard¹,

Deleersnijder²,

Daniëls³

et al. 2010

J. Neurosci.

109

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Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Inhibition of FK506 Binding Proteins Reduces α-Synuclein Aggregation and Parkinson's Disease-Like Pathology

Gérard¹,

Deleersnijder²,

Daniëls³

et al. 2010

J. Neurosci.

109

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“…Currently there are four FKBPs known that are strongly expressed in the brain and in particular in the substantia nigra: FKBP12, FKBP38, FKBP52, and FKBP65. Several reports have already linked FKBP12 and/or FKBP52 to neurodegeneration (23)(24)(25)(26)(27)(28). The mitochondrial FKBP38 (29) was reported to play a role in neurodegeneration through the regulation of cytochrome c release (30).…”

Section: Parkinson Disease (Pd)mentioning

confidence: 99%

Comparative Analysis of Different Peptidyl-Prolyl Isomerases Reveals FK506-binding Protein 12 as the Most Potent Enhancer of α-Synuclein Aggregation

Deleersnijder

Rompuy

Desender

et al. 2011

Journal of Biological Chemistry

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FK506-binding proteins (FKBPs) are members of the immunophilins, enzymes that assist protein folding with their peptidyl-prolyl isomerase (PPIase) activity. Some non-immunosuppressive inhibitors of these enzymes have neuroregenerative and neuroprotective properties with an unknown mechanism of action. We have previously shown that FKBPs accelerate the aggregation of ␣-synuclein (␣-SYN) in vitro and in a neuronal cell culture model for synucleinopathy. In this study we investigated whether acceleration of ␣-SYN aggregation is specific for the FKBP or even the PPIase family. Therefore, we studied the effect of several physiologically relevant PPIases, namely FKBP12, FKBP38, FKBP52, FKBP65, Pin1, and cyclophilin A, on ␣-SYN aggregation in vitro and in neuronal cell culture. Among all PPIases tested in vitro, FKBP12 accelerated ␣-SYN aggregation the most. Furthermore, only FKBP12 accelerated ␣-SYN fibril formation at subnanomolar concentrations, pointing toward an enzymatic effect. Although stable overexpression of various FKBPs enhanced the aggregation of ␣-SYN and cell death in cell culture, they were less potent than FKBP12. When FKBP38, FKBP52, and FKBP65 were overexpressed in a stable FKBP12 knockdown cell line, they could not fully restore the number of ␣-SYN inclusion-positive cells. Both in vitro and cell culture data provide strong evidence that FKBP12 is the most important PPIase modulating ␣-SYN aggregation and validate the protein as an interesting drug target for Parkinson disease. Parkinson disease (PD)2 is the second most common neurodegenerative disorder. Accumulating evidence points to a causative role for the protein ␣-synuclein (␣-SYN) in PD (1-13), but the exact relationship between ␣-SYN aggregation and pathogenesis remains unresolved.We have recently shown that FKBP12, a member of the FK506-binding proteins (FKBPs), accelerates the aggregation of ␣-SYN in vitro (14). Furthermore, we demonstrated that FKBP12 and FKBP52 also enhance the aggregation of ␣-SYN in a neuronal cell culture model for synucleinopathy (15). FK506, a small molecule inhibitor of the FKBPs, counteracts this effect in a dose-dependent way. In addition, knockdown of FKBP12 and FKBP52 decreased the number of ␣-SYN aggregates in this cellular model and protected against cell death.FKBP12 and FKBP52 belong to the human FKBP family, of which currently 15 members have been identified. FKBPs are members of the immunophilins. These are enzymes that bind immunosuppressant drugs such as FK506 and have a peptidylprolyl cis-trans isomerase (PPIase) activity (16). They are able to accelerate the interconversion of cis-trans isomers of Xaa-Pro peptide bonds. This is an energy-demanding step in protein folding (17). Several other functions have also been assigned to the human FKBP family, such as regulation of Ca 2ϩ levels in muscles (18,19), regulation of immune activation (20), and chemotropic nerve guidance (21). In addition, it was also shown that immunophilin ligands, such as FK506, exhibit significant neuroregenerative and neuroprotec...

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“…In several animal models simulating Parkinson's disease, dementia and surgical damage, it has been reported that immunophilin ligands induces sprouting by acting as neurotrophic agents and preventing nerve damage [61]. FKBP12 might be protective due to its action of binding to and stabilising inositol trisphosphate (IP3) and ryanodine calcium channels [8,10], since an increase in intracellular calcium levels has been linked to neuronal death [2].…”

Section: Neuroprotective Actions Of Fk506mentioning

confidence: 99%

“…FK506 and rapamycin show their effects via binding to a class of immunophilin called FK506-binding proteins (FKBP), designated according to their molecular weight: FKBP12, 25, 52, etc. FKBP52 is also known as FKBP59 or heat shock protein 56 and is a component of steroid receptor complexes [2]. Cyclosporin A shows its effects via binding to cyclophilin [72].…”

Section: Introductionmentioning

confidence: 99%

Immunophilin ligands in peripheral nerve regeneration

Kandemir

Sarıkcıoğlu

2015

Folia Morphol

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Immunophilins and their ligands: insights into survival and growth of human neurons

Cited by 35 publications

References 26 publications

Inhibition of FK506 Binding Proteins Reduces α-Synuclein Aggregation and Parkinson's Disease-Like Pathology

Inhibition of FK506 Binding Proteins Reduces α-Synuclein Aggregation and Parkinson's Disease-Like Pathology

Comparative Analysis of Different Peptidyl-Prolyl Isomerases Reveals FK506-binding Protein 12 as the Most Potent Enhancer of α-Synuclein Aggregation

Immunophilin ligands in peripheral nerve regeneration

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