Skip to main content

Advertisement

SpringerLink
Log in

FKBP51 modulates hippocampal size and function in post-translational regulation of Parkin

  • Original Article
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

FK506-binding protein 51 (encoded by Fkpb51, also known as Fkbp5) has been associated with stress-related mental illness. To investigate its function, we studied the morphological consequences of Fkbp51 deletion. Artificial Intelligence-assisted morphological analysis revealed that male Fkbp51 knock-out (KO) mice possess more elongated dentate gyrus (DG) but shorter hippocampal height in coronal sections when compared to WT. Primary cultured Fkbp51 KO hippocampal neurons were shown to exhibit larger dendritic outgrowth than wild-type (WT) controls and pharmacological manipulation experiments suggest that this may occur through the regulation of microtubule-associated protein. Both in vitro primary culture and in vivo labeling support a role for FKBP51 in the regulation of microtubule-associated protein expression. Furthermore, Fkbp51 KO hippocampi exhibited decreases in βIII-tubulin, MAP2, and Tau protein levels, but a greater than 2.5-fold increase in Parkin protein. Overexpression and knock-down FKBP51 demonstrated that FKBP51 negatively regulates Parkin in a dose-dependent and ubiquitin-mediated manner. These results indicate a potential novel post-translational regulatory mechanism of Parkin by FKBP51 and the significance of their interaction on disease onset.

Graphical abstract

  • KO has more flattened hippocampus using AI-assisted measurement

  • Both pyramidal cell layer (PCL) of CA and granular cell layer (GCL) of DG distinguishable as two layers: deep cell layer and superficial layer. Distinct MAP2 expression between deep and superficial layer between KO and WT,

  • Higher Parkin expression in KO brain

  • Mechanism of FKBP51 inhibition resulting in Parkin, MAP2, Tau, and Tubulin expression differences between KO and WT mice, and resulting neurite outgrowth differences.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Availability of data and materials

All data will be available for the public after publication. No large data set needs to be deposited into the public repository.

References

  1. Arlt S, Demiralay C, Tharun B, Geisel O, Storm N, Eichenlaub M, Lehmbeck JT, Wiedemann K, Leuenberger B, Jahn H (2013) Genetic risk factors for depression in Alzheimer’s disease patients. Curr Alzheimer Res 10:72–81

    CAS  PubMed  Google Scholar 

  2. Ashbrook DG, Williams RW, Lu L, Stein JL, Hibar DP, Nichols TE, Medland SE, Thompson PM, Hager R (2014) Joint genetic analysis of hippocampal size in mouse and human identifies a novel gene linked to neurodegenerative disease. BMC Genom 15:850

    Article  Google Scholar 

  3. Barnes AP, Polleux F (2009) Establishment of axon-dendrite polarity in developing neurons. Annu Rev Neurosci 32:347–381

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Binder EB, Bradley RG, Liu W, Epstein MP, Deveau TC, Mercer KB, Tang Y, Gillespie CF, Heim CM, Nemeroff CB, Schwartz AC, Cubells JF, Ressler KJ (2008) Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. JAMA 299:1291–1305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Blair LJ, Criado-Marrero M, Zheng D, Wang X, Kamath S, Nordhues BA, Weeber EJ, Dickey CA (2019) The disease-associated chaperone FKBP51 impairs cognitive function by accelerating AMPA receptor recycling. eNeuro 6

  6. Blair LJ, Nordhues BA, Hill SE, Scaglione KM, O’Leary JC 3rd, Fontaine SN, Breydo L, Zhang B, Li P, Wang L, Cotman C, Paulson HL, Muschol M, Uversky VN, Klengel T, Binder EB, Kayed R, Golde TE, Berchtold N, Dickey CA (2013) Accelerated neurodegeneration through chaperone-mediated oligomerization of tau. J Clin Investig 123:4158–4169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Blair LJ, Zhang B, Dickey CA (2013) Potential synergy between tau aggregation inhibitors and tau chaperone modulators. Alzheimers Res Ther. 5:41

    Article  PubMed  PubMed Central  Google Scholar 

  8. Buee L, Bussiere T, Buee-Scherrer V, Delacourte A, Hof PR (2000) Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res Brain Res Rev 33:95–130

    Article  CAS  PubMed  Google Scholar 

  9. Cartelli D, Amadeo A, Calogero AM, Casagrande FVM, De Gregorio C, Gioria M, Kuzumaki N, Costa I, Sassone J, Ciammola A, Hattori N, Okano H, Goldwurm S, Roybon L, Pezzoli G, Cappelletti G (2018) Parkin absence accelerates microtubule aging in dopaminergic neurons. Neurobiol Aging 61:66–74

    Article  CAS  PubMed  Google Scholar 

  10. Chambraud B, Belabes H, Fontaine-Lenoir V, Fellous A, Baulieu EE (2007) The immunophilin FKBP52 specifically binds to tubulin and prevents microtubule formation. FASEB J 21:2787–2797

    Article  CAS  PubMed  Google Scholar 

  11. Chang YC, Nalbant P, Birkenfeld J, Chang ZF, Bokoch GM (2008) GEF-H1 couples nocodazole-induced microtubule disassembly to cell contractility via RhoA. Mol Biol Cell 19:2147–2153

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Chaugule VK, Walden H (2016) Specificity and disease in the ubiquitin system. Biochem Soc Trans 44:212–227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Chew KC, Matsuda N, Saisho K, Lim GG, Chai C, Tan HM, Tanaka K, Lim KL (2011) Parkin mediates apparent E2-independent monoubiquitination in vitro and contains an intrinsic activity that catalyzes polyubiquitination. PLoS ONE 6:e19720

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Conrad CD, Ortiz JB, Judd JM (2017) Chronic stress and hippocampal dendritic complexity: methodological and functional considerations. Physiol Behav 178:66–81

    Article  CAS  PubMed  Google Scholar 

  15. Corti O, Lesage S, Brice A (2011) What genetics tells us about the causes and mechanisms of Parkinson’s disease. Physiol Rev 91:1161–1218

    Article  CAS  PubMed  Google Scholar 

  16. Courchet J, Lewis TL Jr, Lee S, Courchet V, Liou DY, Aizawa S, Polleux F (2013) Terminal axon branching is regulated by the LKB1-NUAK1 kinase pathway via presynaptic mitochondrial capture. Cell 153:1510–1525

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Dannlowski U, Grabe HJ, Wittfeld K, Klaus J, Konrad C, Grotegerd D, Redlich R, Suslow T, Opel N, Ohrmann P, Bauer J, Zwanzger P, Laeger I, Hohoff C, Arolt V, Heindel W, Deppe M, Domschke K, Hegenscheid K, Volzke H, Stacey D, H. Meyer Zu Schwabedissen, H. Kugel, and B.T. Baune. (2015) Multimodal imaging of a tescalcin (TESC)-regulating polymorphism (rs7294919)-specific effects on hippocampal gray matter structure. Mol Psychiatry 20:398–404

    Article  CAS  PubMed  Google Scholar 

  18. Darios F, Corti O, Lucking CB, Hampe C, Muriel MP, Abbas N, Gu WJ, Hirsch EC, Rooney T, Ruberg M, Brice A (2003) Parkin prevents mitochondrial swelling and cytochrome c release in mitochondria-dependent cell death. Hum Mol Genet 12:517–526

    Article  CAS  PubMed  Google Scholar 

  19. Eichenbaum H (2000) A cortical-hippocampal system for declarative memory. Nat Rev Neurosci 1:41–50

    Article  CAS  PubMed  Google Scholar 

  20. Ekholm-Reed S, Goldberg MS, Schlossmacher MG, Reed SI (2013) Parkin-dependent degradation of the F-box protein Fbw7beta promotes neuronal survival in response to oxidative stress by stabilizing Mcl-1. Mol Cell Biol 33:3627–3643

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Fani N, Gutman D, Tone EB, Almli L, Mercer KB, Davis J, Glover E, Jovanovic T, Bradley B, Dinov ID, Zamanyan A, Toga AW, Binder EB, Ressler KJ (2013) FKBP5 and attention bias for threat: associations with hippocampal function and shape. JAMA Psychiat 70:392–400

    Article  CAS  Google Scholar 

  22. Fani N, King TZ, Shin J, Srivastava A, Brewster RC, Jovanovic T, Bradley B, Ressler KJ (2016) Structural and functional connectivity in posttraumatic stress disorder: associations with Fkbp5. Depress Anxiety 33:300–307

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ferreira TA, Blackman AV, Oyrer J, Jayabal S, Chung AJ, Watt AJ, Sjostrom PJ, van Meyel DJ (2014) Neuronal morphometry directly from bitmap images. Nat Methods 11:982–984

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Gaali S, Kirschner A, Cuboni S, Hartmann J, Kozany C, Balsevich G, Namendorf C, Fernandez-Vizarra P, Sippel C, Zannas AS, Draenert R, Binder EB, Almeida OF, Ruhter G, Uhr M, Schmidt MV, Touma C, Bracher A, Hausch F (2015) Selective inhibitors of the FK506-binding protein 51 by induced fit. Nat Chem Biol 11:33–37

    Article  CAS  PubMed  Google Scholar 

  25. Gerritsen L, Milaneschi Y, Vinkers CH, van Hemert AM, van Velzen L, Schmaal L, Penninx BW (2017) HPA axis genes, and their interaction with childhood maltreatment, are related to cortisol levels and stress-related phenotypes. Neuropsychopharmacology 42:2446–2455

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, Giuffra L, Haynes A, Irving N, James L et al (1991) Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 349:704–706

    Article  CAS  PubMed  Google Scholar 

  27. Gomez TM, Letourneau PC (2014) Actin dynamics in growth cone motility and navigation. J Neurochem 129:221–234

    Article  CAS  PubMed  Google Scholar 

  28. Gu H, Cao Y, Qiu B, Zhou Z, Deng R, Chen Z, Li R, Li X, Wei Q, Xia X, Yong W (2016) Establishment and phenotypic analysis of an Mstn knockout rat. Biochem Biophys Res Commun 477:115–122

    Article  CAS  PubMed  Google Scholar 

  29. Hibar DP, Adams HHH, Jahanshad N, Chauhan G, Stein JL, Hofer E, Renteria ME, Bis JC, Arias-Vasquez A, Ikram MK, Desrivieres S, Vernooij MW, Abramovic L, Alhusaini S, Amin N, Andersson M, Arfanakis K, Aribisala BS, Armstrong NJ, Athanasiu L, Axelsson T, Beecham AH, Beiser A, Bernard M, Blanton SH, Bohlken MM, Boks MP, Bralten J, Brickman AM, Carmichael O, Chakravarty MM, Chen Q, Ching CRK, Chouraki V, Cuellar-Partida G, Crivello F, Den Braber A, Doan NT, Ehrlich S, Giddaluru S, Goldman AL, Gottesman RF, Grimm O, Griswold ME, Guadalupe T, Gutman BA, Hass J, Haukvik UK, Hoehn D, Holmes AJ, Hoogman M, Janowitz D, Jia T, Jorgensen KN, Karbalai N, Kasperaviciute D, Kim S, Klein M, Kraemer B, Lee PH, Liewald DCM, Lopez LM, Luciano M, Macare C, Marquand AF, Matarin M, Mather KA, Mattheisen M, McKay DR, Milaneschi Y, Munoz Maniega S, Nho K, Nugent AC, Nyquist P, Loohuis LMO, Oosterlaan J, Papmeyer M, Pirpamer L, Putz B, Ramasamy A, Richards JS, Risacher SL, Roiz-Santianez R, Rommelse N, Ropele S, Rose EJ, Royle NA, Rundek T, Samann PG, Saremi A, Satizabal CL, Schmaal L, Schork AJ, Shen L, Shin J, Shumskaya E, Smith AV, Sprooten E, Strike LT, Teumer A et al (2017) Novel genetic loci associated with hippocampal volume. Nat Commun 8:13624

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Holz NE, Buchmann AF, Boecker R, Blomeyer D, Baumeister S, Wolf I, Rietschel M, Witt SH, Plichta MM, Meyer-Lindenberg A, Banaschewski T, Brandeis D, Laucht M (2015) Role of FKBP5 in emotion processing: results on amygdala activity, connectivity and volume. Brain Struct Funct 220:1355–1368

    Article  CAS  PubMed  Google Scholar 

  31. Horgusluoglu-Moloch E, Risacher SL, Crane PK, Hibar D, Thompson PM, Saykin AJ, Nho K, I. Alzheimer’s Disease Neuroimaging (2019) Genome-wide association analysis of hippocampal volume identifies enrichment of neurogenesis-related pathways. Sci Rep 9:14498

    Article  PubMed  PubMed Central  Google Scholar 

  32. Huang MC, Schwandt ML, Chester JA, Kirchhoff AM, Kao CF, Liang T, Tapocik JD, Ramchandani VA, George DT, Hodgkinson CA, Goldman D, Heilig M (2014) FKBP5 moderates alcohol withdrawal severity: human genetic association and functional validation in knockout mice. Neuropsychopharmacology 39:2029–2038

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kim JM, Lee KH, Jeon YJ, Oh JH, Jeong SY, Song IS, Kim JM, Lee DS, Kim NS (2006) Identification of genes related to Parkinson’s disease using expressed sequence tags. DNA Res 13:275–286

    Article  CAS  PubMed  Google Scholar 

  34. Kremen WS, Prom-Wormley E, Panizzon MS, Eyler LT, Fischl B, Neale MC, Franz CE, Lyons MJ, Pacheco J, Perry ME, Stevens A, Schmitt JE, Grant MD, Seidman LJ, Thermenos HW, Tsuang MT, Eisen SA, Dale AM, Fennema-Notestine C (2010) Genetic and environmental influences on the size of specific brain regions in midlife: the VETSA MRI study. Neuroimage 49:1213–1223

    Article  PubMed  Google Scholar 

  35. LaVoie MJ, Ostaszewski BL, Weihofen A, Schlossmacher MG, Selkoe DJ (2005) Dopamine covalently modifies and functionally inactivates Parkin. Nat Med 11:1214–1221

    Article  CAS  PubMed  Google Scholar 

  36. Lekman M, Laje G, Charney D, Rush AJ, Wilson AF, Sorant AJ, Lipsky R, Wisniewski SR, Manji H, McMahon FJ, Paddock S (2008) The FKBP5-gene in depression and treatment response—an association study in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Cohort. Biol Psychiatry 63:1103–1110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Letourneau PC, Ressler AH (1984) Inhibition of neurite initiation and growth by taxol. J Cell Biol 98:1355–1362

    Article  CAS  PubMed  Google Scholar 

  38. Levy-Gigi E, Szabo C, Kelemen O, Keri S (2013) Association among clinical response, hippocampal volume, and FKBP5 gene expression in individuals with posttraumatic stress disorder receiving cognitive behavioral therapy. Biol Psychiatry 74:793–800

    Article  CAS  PubMed  Google Scholar 

  39. Levy-Gigi E, Szabo C, Richter-Levin G, Keri S (2015) Reduced hippocampal volume is associated with overgeneralization of negative context in individuals with PTSD. Neuropsychology 29:151–161

    Article  PubMed  Google Scholar 

  40. Lieberman R, Armeli S, Scott DM, Kranzler HR, Tennen H, Covault J (2016) FKBP5 genotype interacts with early life trauma to predict heavy drinking in college students. Am J Med Genet B Neuropsychiatr Genet 171:879–887

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Malhi GS, Das P, Outhred T, Dobson-Stone C, Irwin L, Gessler D, Bryant R, Mannie Z (2019) Effect of stress gene-by-environment interactions on hippocampal volumes and cortisol secretion in adolescent girls. Aust N Z J Psychiatry 53:316–325

    Article  PubMed  Google Scholar 

  42. Matosin N, Halldorsdottir T, Binder EB (2018) Understanding the molecular mechanisms underpinning gene by environment interactions in psychiatric disorders: the FKBP5 model. Biol Psychiatry 83:821–830

    Article  CAS  PubMed  Google Scholar 

  43. Matsumoto L, Takuma H, Tamaoka A, Kurisaki H, Date H, Tsuji S, Iwata A (2010) CpG demethylation enhances alpha-synuclein expression and affects the pathogenesis of Parkinson’s disease. PLoS ONE 5:e15522

    Article  PubMed  PubMed Central  Google Scholar 

  44. McWilliams TG, Barini E, Pohjolan-Pirhonen R, Brooks SP, Singh F, Burel S, Balk K, Kumar A, Montava-Garriga L, Prescott AR, Hassoun SM, Mouton-Liger F, Ball G, Hills R, Knebel A, Ulusoy A, Di Monte DA, Tamjar J, Antico O, Fears K, Smith L, Brambilla R, Palin E, Valori M, Eerola-Rautio J, Tienari P, Corti O, Dunnett SB, Ganley IG, Suomalainen A, Muqit MMK (2018) Phosphorylation of Parkin at serine 65 is essential for its activation in vivo. Open Biol 8

  45. Meijering E, Jacob M, Sarria JC, Steiner P, Hirling H, Unser M (2004) Design and validation of a tool for neurite tracing and analysis in fluorescence microscopy images. Cytometry A 58:167–176

    Article  CAS  PubMed  Google Scholar 

  46. Mikolas P, Tozzi L, Doolin K, Farrell C, O’Keane V, Frodl T (2019) Effects of early life adversity and FKBP5 genotype on hippocampal subfields volume in major depression. J Affect Disord 252:152–159

    Article  CAS  PubMed  Google Scholar 

  47. Ming GL, Song H (2005) Adult neurogenesis in the mammalian central nervous system. Annu Rev Neurosci 28:223–250

    Article  CAS  PubMed  Google Scholar 

  48. Na KS, Won E, Kang J, Kim A, Choi S, Kim YK, Lee MS, Ham BJ (2018) Interaction effects of oxytocin receptor gene polymorphism and depression on hippocampal volume. Psychiatry Res Neuroimaging. 282:18–23

    Article  PubMed  Google Scholar 

  49. Nievergelt CM, Maihofer AX, Klengel T, Atkinson EG, Chen CY, Choi KW, Coleman JRI, Dalvie S, Duncan LE, Gelernter J, Levey DF, Logue MW, Polimanti R, Provost AC, Ratanatharathorn A, Stein MB, Torres K, Aiello AE, Almli LM, Amstadter AB, Andersen SB, Andreassen OA, Arbisi PA, Ashley-Koch AE, Austin SB, Avdibegovic E, Babic D, Baekvad-Hansen M, Baker DG, Beckham JC, Bierut LJ, Bisson JI, Boks MP, Bolger EA, Borglum AD, Bradley B, Brashear M, Breen G, Bryant RA, Bustamante AC, Bybjerg-Grauholm J, Calabrese JR, Caldas-de-Almeida JM, Dale AM, Daly MJ, Daskalakis NP, Deckert J, Delahanty DL, Dennis MF, Disner SG, Domschke K, Dzubur-Kulenovic A, Erbes CR, Evans A, Farrer LA, Feeny NC, Flory JD, Forbes D, Franz CE, Galea S, Garrett ME, Gelaye B, Geuze E, Gillespie C, Uka AG, Gordon SD, Guffanti G, Hammamieh R, Harnal S, Hauser MA, Heath AC, Hemmings SMJ, Hougaard DM, Jakovljevic M, Jett M, Johnson EO, Jones I, Jovanovic T, Qin XJ, Junglen AG, Karstoft KI, Kaufman ML, Kessler RC, Khan A, Kimbrel NA, King AP, Koen N, Kranzler HR, Kremen WS, Lawford BR, Lebois LAM, Lewis CE, Linnstaedt SD, Lori A, Lugonja B, Luykx JJ, Lyons MJ, Maples-Keller J, Marmar C, Martin AR et al (2019) International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci. Nat Commun 10:4558

    Article  PubMed  PubMed Central  Google Scholar 

  50. Nold V, Richter N, Hengerer B, Kolassa IT, Allers KA (2021) FKBP5 polymorphisms induce differential glucocorticoid responsiveness in primary CNS cells—first insights from novel humanized mice. Eur J Neurosci 53:402–415

    Article  PubMed  Google Scholar 

  51. O’Leary JC 3rd, Dharia S, Blair LJ, Brady S, Johnson AG, Peters M, Cheung-Flynn J, Cox MB, de Erausquin G, Weeber EJ, Jinwal UK, Dickey CA (2011) A new anti-depressive strategy for the elderly: ablation of FKBP5/FKBP51. PLoS ONE 6:e24840

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Olah J, Vincze O, Virok D, Simon D, Bozso Z, Tokesi N, Horvath I, Hlavanda E, Kovacs J, Magyar A, Szucs M, Orosz F, Penke B, Ovadi J (2011) Interactions of pathological hallmark proteins: tubulin polymerization promoting protein/p25, beta-amyloid, and alpha-synuclein. J Biol Chem 286:34088–34100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Onoue T, Toda H, Nakai Y (2013) Childhood stress and depression. Nihon Shinkei Seishin Yakurigaku Zasshi 33:105–110

    PubMed  Google Scholar 

  54. Pujol N, Mane A, Berge D, Mezquida G, Amoretti S, Perez L, Gonzalez-Pinto A, Barcones F, Cuesta MJ, Sanchez-Tomico G, Vieta E, Castro-Fornieles J, Bernardo M, Parellada M, P.E. GROUP. (2020) Influence of BDNF and MTHFR polymorphisms on hippocampal volume in first-episode psychosis. Schizophr Res 223:345–352

    Article  PubMed  Google Scholar 

  55. Qi R, Luo Y, Zhang L, Weng Y, Surento W, Jahanshad N, Xu Q, Yin Y, Li L, Cao Z, Thompson PM, Lu GM (2020) FKBP5 haplotypes and PTSD modulate the resting-state brain activity in Han Chinese adults who lost their only child. Transl Psychiatry 10:91

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Qiu B, Hu S, Liu L, Chen M, Wang L, Zeng X, Zhu S (2013) CART attenuates endoplasmic reticulum stress response induced by cerebral ischemia and reperfusion through upregulating BDNF synthesis and secretion. Biochem Biophys Res Commun 436:655–659

    Article  CAS  PubMed  Google Scholar 

  57. Qiu B, Luczak SE, Wall TL, Kirchhoff AM, Xu Y, Eng MY, Stewart RB, Shou W, Boehm SL, Chester JA, Yong W, Liang T (2016) The FKBP5 gene affects alcohol drinking in knockout mice and is implicated in alcohol drinking in humans. Int J Mol Sci 17

  58. Qiu B, Xu Y, Wang J, Liu M, Dou L, Deng R, Wang C, Williams KE, Stewart RB, Xie Z, Ren W, Zhao Z, Shou W, Liang T, Yong W (2019) Loss of FKBP5 affects neuron synaptic plasticity: an electrophysiology insight. Neuroscience 402:23–36

    Article  CAS  PubMed  Google Scholar 

  59. Quinta HR, Maschi D, Gomez-Sanchez C, Piwien-Pilipuk G, Galigniana MD (2010) Subcellular rearrangement of hsp90-binding immunophilins accompanies neuronal differentiation and neurite outgrowth. J Neurochem 115:716–734

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Rein T (2020) Peptidylprolylisomerases, protein folders, or scaffolders? The example of FKBP51 and FKBP52. Bioessays e1900250

  61. Rein T (2020) Post-translational modifications and stress adaptation: the paradigm of FKBP51. Biochem Soc Trans 48:441–449

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Ren Y, Jiang H, Yang F, Nakaso K, Feng J (2009) Parkin protects dopaminergic neurons against microtubule-depolymerizing toxins by attenuating microtubule-associated protein kinase activation. J Biol Chem 284:4009–4017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Ren Y, Zhao J, Feng J (2003) Parkin binds to alpha/beta tubulin and increases their ubiquitination and degradation. J Neurosci 23:3316–3324

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Renteria ME, Hansell NK, Strike LT, McMahon KL, de Zubicaray GI, Hickie IB, Thompson PM, Martin NG, Medland SE, Wright MJ (2014) Genetic architecture of subcortical brain regions: common and region-specific genetic contributions. Genes Brain Behav 13:821–830

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Rother C, Kolmogorov V, Blake A (2004) GrabCut—interactive foreground extraction using iterated graph cuts. ACM Trans Graphics (SIGGRAPH) 23:309–314

    Article  Google Scholar 

  66. Sarraf SA, Raman M, Guarani-Pereira V, Sowa ME, Huttlin EL, Gygi SP, Harper JW (2013) Landscape of the PARKIN-dependent ubiquitylome in response to mitochondrial depolarization. Nature 496:372–376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Schiene C, Fischer G (2000) Enzymes that catalyse the restructuring of proteins. Curr Opin Struct Biol 10:40–45

    Article  CAS  PubMed  Google Scholar 

  68. Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, Preibisch S, Rueden C, Saalfeld S, Schmid B, Tinevez JY, White DJ, Hartenstein V, Eliceiri K, Tomancak P, Cardona A (2012) Fiji: an open-source platform for biological-image analysis. Nat Methods 9:676–682

    Article  CAS  PubMed  Google Scholar 

  69. Schmidt MV, Paez-Pereda M, Holsboer F, Hausch F (2012) The prospect of FKBP51 as a drug target. ChemMedChem 7:1351–1359

    Article  CAS  PubMed  Google Scholar 

  70. Schmidt U, Buell DR, Ionescu IA, Gassen NC, Holsboer F, Cox MB, Novak B, Huber C, Hartmann J, Schmidt MV, Touma C, Rein T, Herrmann L (2015) A role for synapsin in FKBP51 modulation of stress responsiveness: Convergent evidence from animal and human studies. Psychoneuroendocrinology 52:43–58

    Article  CAS  PubMed  Google Scholar 

  71. Slomianka L, Amrein I, Knuesel I, Sorensen JC, Wolfer DP (2011) Hippocampal pyramidal cells: the reemergence of cortical lamination. Brain Struct Funct 216:301–317

    Article  PubMed  PubMed Central  Google Scholar 

  72. Smith ME (2005) Bilateral hippocampal volume reduction in adults with post-traumatic stress disorder: a meta-analysis of structural MRI studies. Hippocampus 15:798–807

    Article  PubMed  Google Scholar 

  73. Soltesz I, Losonczy A (2018) CA1 pyramidal cell diversity enabling parallel information processing in the hippocampus. Nat Neurosci 21:484–493

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Szymanska M, Budziszewska B, Jaworska-Feil L, Basta-Kaim A, Kubera M, Leskiewicz M, Regulska M, Lason W (2009) The effect of antidepressant drugs on the HPA axis activity, glucocorticoid receptor level and FKBP51 concentration in prenatally stressed rats. Psychoneuroendocrinology 34:822–832

    Article  CAS  PubMed  Google Scholar 

  75. Takahashi K, Uchida C, Shin RW, Shimazaki K, Uchida T (2008) Prolyl isomerase, Pin1: new findings of post-translational modifications and physiological substrates in cancer, asthma and Alzheimer’s disease. Cell Mol Life Sci 65:359–375

    Article  CAS  PubMed  Google Scholar 

  76. Tatro ET, Nguyen TB, Bousman CA, Masliah E, Grant I, Atkinson JH, Everall IP (2010) Correlation of major depressive disorder symptoms with FKBP5 but not FKBP4 expression in human immunodeficiency virus-infected individuals. J Neurovirol 16:399–404

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Thompson PM, Hayashi KM, De Zubicaray GI, Janke AL, Rose SE, Semple J, Hong MS, Herman DH, Gravano D, Doddrell DM, Toga AW (2004) Mapping hippocampal and ventricular change in Alzheimer disease. Neuroimage 22:1754–1766

    Article  PubMed  Google Scholar 

  78. Tsechpenakis G, Chatzis SP (2011) Deformable probability maps: Probabilistic shape and appearance-based object segmentation. Comput Vis Image Underst 115:1157–1169

    Article  Google Scholar 

  79. Wagner KV, Marinescu D, Hartmann J, Wang XD, Labermaier C, Scharf SH, Liebl C, Uhr M, Holsboer F, Muller MB, Schmidt MV (2012) Differences in FKBP51 regulation following chronic social defeat stress correlate with individual stress sensitivity: influence of paroxetine treatment. Neuropsychopharmacology 37:2797–2808

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Wang C, Shen M, Guillaume B, Chong YS, Chen H, Fortier MV, Meaney MJ, Qiu A (2018) FKBP5 moderates the association between antenatal maternal depressive symptoms and neonatal brain morphology. Neuropsychopharmacology 43:564–570

    Article  CAS  PubMed  Google Scholar 

  81. Wang Y, Qiu B, Liu J, Zhu WG, Zhu S (2014) Cocaine- and amphetamine-regulated transcript facilitates the neurite outgrowth in cortical neurons after oxygen and glucose deprivation through PTN-dependent pathway. Neuroscience 277:103–110

    Article  CAS  PubMed  Google Scholar 

  82. Williams JA, Ni HM, Ding Y, Ding WX (2015) Parkin regulates mitophagy and mitochondrial function to protect against alcohol-induced liver injury and steatosis in mice. Am J Physiol Gastrointest Liver Physiol 309:G324-340

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Wilson C, Gonzalez-Billault C (2015) Regulation of cytoskeletal dynamics by redox signaling and oxidative stress: implications for neuronal development and trafficking. Front Cell Neurosci 9:381

    Article  PubMed  PubMed Central  Google Scholar 

  84. Xie P, Kranzler HR, Poling J, Stein MB, Anton RF, Farrer LA, Gelernter J (2010) Interaction of FKBP5 with childhood adversity on risk for post-traumatic stress disorder. Neuropsychopharmacology 35:1684–1692

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Xing Y, Hou J, Meng Q, Yang M, Kurihara H, Tian J (2015) Novel antidepressant candidate RO-05 modulated glucocorticoid receptors activation and FKBP5 expression in chronic mild stress model in rats. Neuroscience 290:255–265

    Article  CAS  PubMed  Google Scholar 

  86. Xu K, Zhong G, Zhuang X (2013) Actin, spectrin, and associated proteins form a periodic cytoskeletal structure in axons. Science 339:452–456

    Article  CAS  PubMed  Google Scholar 

  87. Yadaw AS, Siddiq MM, Rabinovich V, Tolentino R, Hansen J, Iyengar R (2019) Dynamic balance between vesicle transport and microtubule growth enables neurite outgrowth. PLoS Comput Biol 15:e1006877

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Yang F, Jiang Q, Zhao J, Ren Y, Sutton MD, Feng J (2005) Parkin stabilizes microtubules through strong binding mediated by three independent domains. J Biol Chem 280:17154–17162

    Article  CAS  PubMed  Google Scholar 

  89. Yang Y, Nishimura I, Imai Y, Takahashi R, Lu B (2003) Parkin suppresses dopaminergic neuron-selective neurotoxicity induced by Pael-R in Drosophila. Neuron 37:911–924

    Article  CAS  PubMed  Google Scholar 

  90. Yogev S, Cooper R, Fetter R, Horowitz M, Shen K (2016) Microtubule organization determines axonal transport dynamics. Neuron 92:449–460

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Yong W, Yang Z, Periyasamy S, Chen H, Yucel S, Li W, Lin LY, Wolf IM, Cohn MJ, Baskin LS, Sanchez ER, Shou W (2007) Essential role for co-chaperone Fkbp52 but not Fkbp51 in androgen receptor-mediated signaling and physiology. J Biol Chem 282:5026–5036

    Article  CAS  PubMed  Google Scholar 

  92. Yun JY, Jin MJ, Kim S, Lee SH (2020) Stress-related cognitive style is related to volumetric change of the hippocampus and FK506 binding protein 5 polymorphism in post-traumatic stress disorder. Psychol Med 1–12

  93. Zannas AS, Jia M, Hafner K, Baumert J, Wiechmann T, Pape JC, Arloth J, Kodel M, Martinelli S, Roitman M, Roh S, Haehle A, Emeny RT, Iurato S, Carrillo-Roa T, Lahti J, Raikkonen K, Eriksson JG, Drake AJ, Waldenberger M, Wahl S, Kunze S, Lucae S, Bradley B, Gieger C, Hausch F, Smith AK, Ressler KJ, Muller-Myhsok B, Ladwig KH, Rein T, Gassen NC, Binder EB (2019) Epigenetic upregulation of FKBP5 by aging and stress contributes to NF-kappaB-driven inflammation and cardiovascular risk. Proc Natl Acad Sci USA 116:11370–11379

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Zhang T, Hou C, Zhang S, Liu S, Li Z, Gao J (2019) Lgl1 deficiency disrupts hippocampal development and impairs cognitive performance in mice. Genes Brain Behav 18:e12605

    Article  CAS  PubMed  Google Scholar 

  95. Zuiderveld K (1994) Contrast limited adaptive histogram equalization. In: Heckbert PS (ed) Graphic gems IV. Academic Press, New York

    Google Scholar 

Download references

Acknowledgements

We would also like to express our appreciation to Indiana Alcohol Research Center and Dr. Weinian Shou for the support in initiating this long-term project.

Funding

This research was supported by grants from Institute of Integrative Artificial Intelligence (iAI) seed funding—IUPUI, CAMS Innovation Fund for Medical Sciences (CIFMS) (2017-I2M-3-015) and the National Science Foundation of China (nos. 81700751 and 2013CB945001).

Author information

Author notes

  1. Bin Qiu and Zhaohui Zhong contributed equally to this work.

Authors and Affiliations

  1. Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    Weidong Yong

  2. Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China

    Bin Qiu, Yuxue Xu, Jun Wang, Ran Deng, Chao Wang & Weidong Yong

  3. Department of General Surgery, Peking University People’s Hospital, Beijing, 100032, China

    Zhaohui Zhong

  4. Department of Computer and Information Science, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202, USA

    Shawn Righter & Gavriil Tsechpenakis

  5. Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    Kent E. Williams & Tiebing Liang

  6. Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    Yao-ying Ma

  7. Department of Pharmacology, Yale University School of Medicine, New Haven, CT, 06520, USA

    Bin Qiu

Authors
  1. Bin Qiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhaohui Zhong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shawn Righter
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yuxue Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jun Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ran Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Chao Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kent E. Williams
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yao-ying Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Gavriil Tsechpenakis
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Tiebing Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Weidong Yong
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Authors contributed to the study conception and design: WY, TL, YM, and GT. Material preparation, data collection and analysis were performed by BQ, ZZ, SR, YX, JW, RD, CW, KEW and GT. Data curation and formal analysis: BQ, ZZ, SR, and KEW, investigation: all authors participated. AI-assisted data analysis methodology: GT and SR. The first draft of the manuscript was written by BQ, TL, and WY and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Funding acquisition: WY and TL.

Corresponding authors

Correspondence to Tiebing Liang or Weidong Yong.

Ethics declarations

Conflict of interest

All authors have no conflicts of interest to declare.

Ethical approval and consent to participate

Animal studies have been reviewed and approved by the Animal Care and Research Advisory Committee of the Institute of Laboratory Animal Sciences at the Chinese Academy of Medical Sciences and the Indiana University School of Medicine. No human samples were included in this study.

Consent for publication

All authors reviewed and agreed to publish the current finding.

Supplementary Information

Below is the link to the electronic supplementary material.

18_2022_4167_MOESM1_ESM.docx

SI-Fig. 1. Morphological differences between KO and WT primary cultured neurons at DIV5. (A) Panel highlights the neurons labeled with anti-βIII-tubulin (red), -F-actin (green), and -DAPI (blue). Fkbp5 KO neurons possess much greater dendritic outgrowth than WT. (B) Triple-immunolabeling for βIII-tubulin (red), Tau (green), and DAPI (blue). SI-Fig. 2. Immunofluorescence (IF) labeling of MAP2 and βIII-tubulin. MAP2 and βIII-tubulin exhibit reduced expression in KO DG and CA1 regions relative to WT. WT DG regions ML and HR have particularly higher expression of MAP2 and tubulin. Notably, an axon-rich sublayer between the granular cell layer and ML possesses more intensive MAP2 labelling in WT. ML: molecular layer; GCL= granule cell layer; HR=Hilar Region; Alv=alveus, Ori= oriens layer; Pyr=pyramidal neuron layer; Rad=radiatum layer; LM= lacunosum-moleculare. SI-Fig. 3. MAP2 and Tau expression in the hippocampus. Brain labeled with mouse anti-MAP2 and mouse anti-Tau antibodies. View of hippocampus and magnified DG and CA1 subregions demonstrate that both MAP2 and Tau are decreased in KO. ML: molecular layer; GCL= granule cell layer; HR=Hilar Region; Alv=alveus, Ori= oriens layer; Pyr=pyramidal neuron layer, Rad=radiatum layer; LM= lacunosum-molecular SI-Fig. 4. Quantification of IHC of MAP2, βIII-tubulin, and Tau protein labeling in Fig. 4. SI-Fig. 5. Cell number comparison in the subfields of hippocampus between Fkbp51 KO mice and WT mice. (A) Ki67 labeled brain counter-stained with Hematoxylin. (B) In each of hippocampal subfield total and positively labeled cells were counted. Average total cell numbers and the percentage of Ki67 positive cells are presented (DOCX 52 KB)

Supplementary file2 (PPTX 163632 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Qiu, B., Zhong, Z., Righter, S. et al. FKBP51 modulates hippocampal size and function in post-translational regulation of Parkin. Cell. Mol. Life Sci. 79, 175 (2022). https://doi.org/10.1007/s00018-022-04167-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00018-022-04167-8

Keywords

Search

Navigation