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Review
. 2020 Dec;15(12):2195-2202.
doi: 10.4103/1673-5374.284980.

Mounting evidence of FKBP12 implication in neurodegeneration

Gabriella Caminati  1 , Piero Procacci  2
Affiliations
Review

Mounting evidence of FKBP12 implication in neurodegeneration

Gabriella Caminati et al. Neural Regen Res. 2020 Dec.

Abstract

Intrinsically disordered proteins, such as tau or α-synuclein, have long been associated with a dysfunctional role in neurodegenerative diseases. In Alzheimer's and Parkinson's' diseases, these proteins, sharing a common chemical-physical pattern with alternating hydrophobic and hydrophilic domains rich in prolines, abnormally aggregate in tangles in the brain leading to progressive loss of neurons. In this review, we present an overview linking the studies on the implication of the peptidyl-prolyl isomerase domain of immunophilins, and notably FKBP12, to a variety of neurodegenerative diseases, focusing on the molecular origin of such a role. The involvement of FKBP12 dysregulation in the aberrant aggregation of disordered proteins pinpoints this protein as a possible therapeutic target and, at the same time, as a predictive biomarker for early diagnosis in neurodegeneration, calling for the development of reliable, fast and cost-effective detection methods in body fluids for community-based screening campaigns.

Keywords: Alzheimer’s disease; FK506 binding protein; FKBP12; Parkinson’s disease; biomarker; detections; neurodegeneration; tau protein; α-synuclein.

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Conflict of interest statement

None

Figures

Figure 1
Figure 1
FKBP12 structure and expression level. FKBP12 tertiary structure (PDB code 1FKG) in complex with a pipecolic ligand (bond representation) H-bonded to Tyr82 and Ile56 highly conserved residues (shown as CPK representation). Below we report the mRNA expression profile for the FKBP1A gene as reported by the BioGPS gene annotation portal http://biogps.org. Rightmost turquoise and magenta bars refer to brain tissue and blood, respectively.
Figure 2
Figure 2
Summary of the research activity on FKBP12 since its discovery as obtained from targeted Scopus interrogations. (A) Time record of the normalized fraction of Scopus-indexed papers containing the keyword “FKBP” in combination with “cancer” (green) or “immuno” (black) or “neuro” (red) or “detection” (blue). (B) Time record number of FKBP papers related to detection and neurodegeneration. The continuous curves are the result of four years window running averages.
Figure 3
Figure 3
Schematic primary sequence of tau protein and α-synuclein (α-syn). In tau protein sequence, TSP indicates the region rich in prolines and phosphorylations T and S sites. R1–R4 is the tubulin-binding region and N1 N2 match the polypeptide sequences encoded by exons 2 and 3. In α-syn the central hydrophobic NAC domain is involved in beta fibrillation. A color-coded scheme is used for hydrophobicity (grey: hydrophobic, red: hydrophilic). Proline residues are indicated by green bars.
Figure 4
Figure 4
Fluorescence images for the system FKBP12/α-syn after 23 days at 37°C at constant α-syn concentration and increasing FKBP12 content. (A) Mature fibrils of pure α-syn. (B) Branched aggregated structures for FKBP12/α-syn 0.6:1 mixture. (C) Dendritic explosion of branched aggregates for the FKBP12/α-syn 1:1 mixture. Scale bars: 50 μm. Adapted from Caminati et al., 2019. α-syn: α-Synuclein.
Figure 5
Figure 5
Mechanism for FKBP12-driven aggregation of α-syn. On the left, a ribbon representation of α-syn bound to FKBP12. The NAC domain in α-syn is highlighted in light salmon color. In orange, we show the Try82 and Ile56 of the catalytic site of FKBP12 interacting with an α-syn Pro at the C terminus. On the right, we show how, when bound to α-syn hydrophilic C terminus, FKBP12 promotes branched fibrillar growth with beta stacking of the α-syn NAC domains. α-syn: α-Synuclein.
Figure 6
Figure 6
Cartoon depicting the sensor strategy adopted for FKBP12 quantification in biofluids. FKBP12 present in fluids in contact with the nanoplatform is captured by the receptor and immobilized on the surface of the nanoplatform where it can easily be quantitatively measured. Adapted from Caminati et al. (2019).
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