Pin1 Mediates Aβ-induced Dendritic Spine Loss

Overview

Journal Sci Signal

Specialties Cell Biology
Physiology
Science

Date 2018 Mar 22

PMID 29559586

Citations 21

Authors

Nancy R Stallings

Melissa A ONeal

Jie Hu

Ege T Kavalali

Ilya Bezprozvanny

James S Malter

Affiliations

Soon will be listed here.

Abstract

Early-stage Alzheimer's disease is characterized by the loss of dendritic spines in the neocortex of the brain. This phenomenon precedes tau pathology, plaque formation, and neurodegeneration and likely contributes to synaptic loss, memory impairment, and behavioral changes in patients. Studies suggest that dendritic spine loss is induced by soluble, multimeric amyloid-β (Aβ), which, through postsynaptic signaling, activates the protein phosphatase calcineurin. We investigated how calcineurin caused spine pathology and found that the cis-trans prolyl isomerase Pin1 was a critical downstream target of Aβ-calcineurin signaling. In dendritic spines, Pin1 interacted with and was dephosphorylated by calcineurin, which rapidly suppressed its isomerase activity. Knockout of Pin1 or exposure to Aβ induced the loss of mature dendritic spines, which was prevented by exogenous Pin1. The calcineurin inhibitor FK506 blocked dendritic spine loss in Aβ-treated wild-type cells but had no effect on -null neurons. These data implicate Pin1 in dendritic spine maintenance and synaptic loss in early Alzheimer's disease.

Citing Articles

Pin1-catalyzed conformational regulation after phosphorylation: A distinct checkpoint in cell signaling and drug discovery.

Lu K, Zhou X Sci Signal. 2024; 17(841):eadi8743.

PMID: 38889227 PMC: 11409840. DOI: 10.1126/scisignal.adi8743.

Potential prognostic value of CSF-targeted proteomics across the Alzheimer's disease continuum.

Xu B, Ling Y, Liu L, Liu Y, Lin Y, Lyu J BMC Geriatr. 2024; 24(1):501.

PMID: 38844858 PMC: 11157758. DOI: 10.1186/s12877-024-05104-z.

Cognitive integrity in Non-Demented Individuals with Alzheimer's Neuropathology is associated with preservation and remodeling of dendritic spines.

Guptarak J, Scaduto P, Tumurbaatar B, Zhang W, Jupiter D, Taglialatela G Alzheimers Dement. 2024; 20(7):4677-4691.

PMID: 38829680 PMC: 11247701. DOI: 10.1002/alz.13900.

Alzheimer-like behavior and synaptic dysfunction in 3 × Tg-AD mice are reversed with calcineurin inhibition.

Zeng J, Hu X, Sun D, Hong X, Ma J, Feng Q Exp Brain Res. 2024; 242(6):1507-1515.

PMID: 38719948 DOI: 10.1007/s00221-024-06841-8.

Epigenetic Regulation of Neuroinflammation in Alzheimer's Disease.

Ma Y, Wang W, Liu S, Qiao X, Xing Y, Zhou Q Cells. 2024; 13(1).

PMID: 38201283 PMC: 10778497. DOI: 10.3390/cells13010079.

References

Lu P, Wulf G, Zhou X, Davies P, Lu K . The prolyl isomerase Pin1 restores the function of Alzheimer-associated phosphorylated tau protein. Nature. 1999; 399(6738):784-8. DOI: 10.1038/21650. View

Geer L, Markey S, Kowalak J, Wagner L, Xu M, Maynard D . Open mass spectrometry search algorithm. J Proteome Res. 2004; 3(5):958-64. DOI: 10.1021/pr0499491. View

Shankar G, Walsh D . Alzheimer's disease: synaptic dysfunction and Abeta. Mol Neurodegener. 2009; 4:48. PMC: 2788538. DOI: 10.1186/1750-1326-4-48. View

Lu K, Zhou X . The prolyl isomerase PIN1: a pivotal new twist in phosphorylation signalling and disease. Nat Rev Mol Cell Biol. 2007; 8(11):904-16. DOI: 10.1038/nrm2261. View

Westmark P, Westmark C, Jeevananthan A, Malter J . Preparation of synaptoneurosomes from mouse cortex using a discontinuous percoll-sucrose density gradient. J Vis Exp. 2011; (55). PMC: 3230173. DOI: 10.3791/3196. View

Rodriguez A, Ehlenberger D, Dickstein D, Hof P, Wearne S . Automated three-dimensional detection and shape classification of dendritic spines from fluorescence microscopy images. PLoS One. 2008; 3(4):e1997. PMC: 2292261. DOI: 10.1371/journal.pone.0001997. View

Sosa L, Malter J, Hu J, Bustos Plonka F, Oksdath M, Nieto Guil A . Protein interacting with NIMA (never in mitosis A)-1 regulates axonal growth cone adhesion and spreading through myristoylated alanine-rich C kinase substrate isomerization. J Neurochem. 2016; 137(5):744-55. DOI: 10.1111/jnc.13612. View

Trudgian D, Thomas B, McGowan S, Kessler B, Salek M, Acuto O . CPFP: a central proteomics facilities pipeline. Bioinformatics. 2010; 26(8):1131-2. DOI: 10.1093/bioinformatics/btq081. View

Verdecia M, Bowman M, Lu K, Hunter T, Noel J . Structural basis for phosphoserine-proline recognition by group IV WW domains. Nat Struct Biol. 2000; 7(8):639-43. DOI: 10.1038/77929. View

10.

Rangasamy V, Mishra R, Sondarva G, Das S, Lee T, Bakowska J . Mixed-lineage kinase 3 phosphorylates prolyl-isomerase Pin1 to regulate its nuclear translocation and cellular function. Proc Natl Acad Sci U S A. 2012; 109(21):8149-54. PMC: 3361382. DOI: 10.1073/pnas.1200804109. View

11.

Galas M, Dourlen P, Begard S, Ando K, Blum D, Hamdane M . The peptidylprolyl cis/trans-isomerase Pin1 modulates stress-induced dephosphorylation of Tau in neurons. Implication in a pathological mechanism related to Alzheimer disease. J Biol Chem. 2006; 281(28):19296-304. DOI: 10.1074/jbc.M601849200. View

12.

Shankar G, Li S, Mehta T, Garcia-Munoz A, Shepardson N, Smith I . Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nat Med. 2008; 14(8):837-42. PMC: 2772133. DOI: 10.1038/nm1782. View

13.

Eckerdt F, Yuan J, Saxena K, Martin B, Kappel S, Lindenau C . Polo-like kinase 1-mediated phosphorylation stabilizes Pin1 by inhibiting its ubiquitination in human cells. J Biol Chem. 2005; 280(44):36575-83. DOI: 10.1074/jbc.M504548200. View

14.

Ranganathan R, Lu K, Hunter T, Noel J . Structural and functional analysis of the mitotic rotamase Pin1 suggests substrate recognition is phosphorylation dependent. Cell. 1997; 89(6):875-86. DOI: 10.1016/s0092-8674(00)80273-1. View

15.

Craig R, Beavis R . TANDEM: matching proteins with tandem mass spectra. Bioinformatics. 2004; 20(9):1466-7. DOI: 10.1093/bioinformatics/bth092. View

16.

Scheff S, Price D . Alzheimer's disease-related alterations in synaptic density: neocortex and hippocampus. J Alzheimers Dis. 2006; 9(3 Suppl):101-15. DOI: 10.3233/jad-2006-9s312. View

17.

Zhuo M, Zhang W, Son H, Mansuy I, Sobel R, Seidman J . A selective role of calcineurin aalpha in synaptic depotentiation in hippocampus. Proc Natl Acad Sci U S A. 1999; 96(8):4650-5. PMC: 16387. DOI: 10.1073/pnas.96.8.4650. View

18.

Kimura T, Tsutsumi K, Taoka M, Saito T, Masuda-Suzukake M, Ishiguro K . Isomerase Pin1 stimulates dephosphorylation of tau protein at cyclin-dependent kinase (Cdk5)-dependent Alzheimer phosphorylation sites. J Biol Chem. 2013; 288(11):7968-7977. PMC: 3597833. DOI: 10.1074/jbc.M112.433326. View

19.

Pastorino L, Sun A, Lu P, Zhou X, Balastik M, Finn G . The prolyl isomerase Pin1 regulates amyloid precursor protein processing and amyloid-beta production. Nature. 2006; 440(7083):528-34. DOI: 10.1038/nature04543. View

20.

Nakamura K, Kosugi I, Lee D, Hafner A, Sinclair D, Ryo A . Prolyl isomerase Pin1 regulates neuronal differentiation via β-catenin. Mol Cell Biol. 2012; 32(15):2966-78. PMC: 3434519. DOI: 10.1128/MCB.05688-11. View