Biology of Degenerative Diseases Lab

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Biology of Degenerative Diseases Lab

Research

Research

Overview

We speculate that each of approximately 150 chaperone proteins could be a drug target for human diseases. Our lab is focused on chaperones capable of modulating the progression and toxicity of tauopathies, a group more than 15 neurodegenerative diseases (including Alzheimer’s disease) characterized by aberrant accumulation of aggregates of the tau protein. Our work has also explored chaperone involvement in other neuropsychiatric disorders including depression and PTSD. Our lab is involved in drug development and target validation for specific chaperone proteins and we hope to someday soon translate these treatments and insights into clinical practice with the ultimate goal of developing a cure.


  • The Hsp90 cochaperone FKBP51 regulates tau structure and function

    We are working to validate FKBP51 as a target for tauopathies, like Alzheimer’s disease, and explore the molecular landscape by which FKBP51 genetic variants create a vulnerability for neuropsychiatric symptoms. Neuropsychiatric symptoms are often co-morbid with Alzheimer’s disease and other tauopathies correlate with a faster decline in patients.

    PPlases
    Hsp90 co-chaperones colocalize with tau tangles in human Alzheimer’s disease brain.

  • Exploiting molecular chaperones to understand the impact of tau aggregation on prion-like spreading in AD

    Aberrant tau protein accumulates in a fashion that correlates with disease progression and does so through synaptically connected brain regions. However, we still do not understand what properties of tau seeds or cells that propagate these seeds make them susceptible or resilient to spread tau and cause damage. This project focuses on using the cell’s natural defense system, molecular chaperones, as tools to regulate this process. We hope through this work to understand more about the relationship between tau propagation and neuronal damage, as well as identify molecular targets to regulate this process.

  • Controlling FKBP51 for the treatment of PTSD”

    Some individuals are vulnerable to develop PTSD, depression, and other neuropsychiatric disorders following stress exposure due to the presence of common allelic variations in the FKBP5 gene. We want to understand more about the mechanisms underlying this vulnerability and the best way to provide resilience towards this increased risk.

Selected Publications

Criado-Marrero M, Gebru NT, Gould LA, Blazier DM, Vidal Agular, Y, Smith TM, Abdelmaboud SS, Shelton LB, Wang X, Dahrendorff J, Beaulieu-Abdelahad D, Dickey CA, Blair LJ. “FKBP52 overexpression accelerates hippocampal-dependent memory impairments in a tau transgenic mouse model.” NPJ Aging Mech Dis. 2021 May 3;7(1):9. 00062-x. https://www.nature.com/articles/s41514-021-00062-x

Criado-Marrero, M, Gebru, NT, Blazier, DM, Gould LA, Baker JD, Beaulieu-Abdelahad D, Blair LJ. Hsp90 co-chaperones, FKBP52 and Aha1, promote tau pathogenesis in aged wild-type mice. Acta Neuropathol Commun. 2021 Apr 8;9(1):65. https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-021-01159-w

Webster JM, Darling AL, Sanders TA, Blazier DM, Vidal-Aguiar Y, Beaulieu-Abdelahad D, Plemmons DG, Hill SE, Uversky VN, Bickford PC, Dickey CA, Blair LJ. Hsp22 with an N-Terminal Domain Truncation Mediates a Reduction in Tau Protein Levels. Int J Mol Sci. 2020 Jul 30;21(15). https://www.mdpi.com/1422-0067/21/15/5442

Criado-Marrero M., Sabbagh J.J., Jones M.R., Chaput D., Dickey C.A., Blair L.J. Hippocampal Neurogenesis Is Enhanced in Adult Tau Deficient Mice. Cells. 2020, 9, 210. https://www.mdpi.com/2073-4409/9/1/210

Criado-Marrero M, Gebru NT, Gould LA, Smith T, Kim S, Blackburn RJ, Dickey CA, Blair LJ. Early life stress and high FKBP5 interact to increase 2 anxiety-like symptoms through altered AKT signaling in 3 the dorsal hippocampus. Int. J. Mol. Sci.2019, 20(11), 2738. https://www.mdpi.com/1422-0067/20/11/2738/htm

Blair LJ, Criado-Marrero M, Zheng D, Wang X, Kamath S, Nordhues BA, Weeber EJ, Dickey CA. The Disease-Associated Chaperone FKBP51 Impairs Cognitive Function by Accelerating AMPA Receptor Recycling. eNeuro. 2019 Jan-Feb;6(1). eCollection 2019 Jan-Feb. https://www.eneuro.org/content/6/1/ENEURO.0242-18.2019

Blair LJ, Genest O, Mollapour M. The multiple facets of the Hsp90 machine. Nat. Struct. Mol. Biol. 2019 Jan 7. https://www.nature.com/articles/s41594-018-0177-7

Shelton LB, Baker JD, Zheng D, Sullivan LE, Solanki PK, Webster JM, Sun Z, Sabbagh JJ, Nordhues BA, Koren J 3rd, Ghosh S, Blagg BSJ, Blair LJ*, Dickey CA. Hsp90 activator Aha1 drives production of pathological tau aggregates. Proc Natl Acad Sci U S A. 2017 Sep 5;114(36):9707-9712. Epub 2017 Aug 21. https://www.pnas.org/content/114/36/9707.long

Baker JD, Shelton LB, Zheng D, Favretto F, Nordhues BA, Darling A, Sullivan LE, Sun Z, Solanki PK, Martin MD, Suntharalingam A, Sabbagh JJ, Becker S, Mandelkow E, Uversky VN, Zweckstetter M, Dickey CA, Koren J, Blair LJ. Human cyclophilin 40 unravels neurotoxic amyloids. PLoS biology. 15(6) : e2001336, 2017. https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.2001336

Hill SE, Beaulieu-Abdelahad D, Lemus A, Webster JM, Ospina SR, Darling AL, Martin MD, Patel S, Bridenstine L, Swonger R, Paul S, Blackburn R, Calcul L, Dickey CA, Leahy JW, Blair LJ. “Benzothiazole Substitution Analogs of Rhodacyanine Hsp70 Inhibitors Modulate Tau Accumulation.” ACS Chem Biol. 2023 May 19;18(5):1124-1135. https://pubs.acs.org/doi/10.1021/acschembio.2c00919

Gebru NT, Hill SE, Blair LJ. “Genetically Engineered Mouse Models of FK506-Binding Protein 5.” J Cell Biochem. 2023;1‐17. https://onlinelibrary.wiley.com/doi/10.1002/jcb.30374

Hill SE, Esquivel AR, Rodriguez Ospina S, Rahal LM, Dickey CA, Blair LJ. “Chaperoning activity of the cyclophilin family prevents tau aggregation.” Protein Science. 2022 Nov;31(11):e4448. https://onlinelibrary.wiley.com/doi/10.1002/pro.4448

Criado-Marrero M, Blazier DM, Gould LA, Gebru NT, Rodriguez Ospina S, Armendariz DS, Darling AL, Beaulieu-Abdelahad D, Blair LJ. “Evidence against a contribution of the CCAAT-enhancer binding protein homologous protein (CHOP) in mediating neurotoxicity in rTg4510 mice” Scientific Reports. 2022 May 5;12(1):7372. https://www.nature.com/articles/s41598-022-11025-x

Criado-Marrero M, Gebru NT, Gould LA, Blazier DM, Vidal Agular, Y, Smith TM, Abdelmaboud SS, Shelton LB, Wang X, Dahrendorff J, Beaulieu-Abdelahad D, Dickey CA, Blair LJ. “FKBP52 overexpression accelerates hippocampal-dependent memory impairments in a tau transgenic mouse model.” NPJ Aging Mech Dis. 2021 May 3;7(1):9. 00062-x. https://www.nature.com/articles/s41514-021-00062-x

Criado-Marrero, M, Gebru, NT, Blazier, DM, Gould LA, Baker JD, Beaulieu-Abdelahad D, Blair LJ. Hsp90 co-chaperones, FKBP52 and Aha1, promote tau pathogenesis in aged wild-type mice. Acta Neuropathol Commun. 2021 Apr 8;9(1):65. https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-021-01159-w

Blair LJ, Criado-Marrero M, Zheng D, Wang X, Kamath S, Nordhues BA, Weeber EJ, Dickey CA. The Disease-Associated Chaperone FKBP51 Impairs Cognitive Function by Accelerating AMPA Receptor Recycling. eNeuro. 2019 Jan-Feb;6(1). eCollection 2019 Jan-Feb. https://www.eneuro.org/content/6/1/ENEURO.0242-18.2019

Shelton LB, Baker JD, Zheng D, Sullivan LE, Solanki PK, Webster JM, Sun Z, Sabbagh JJ, Nordhues BA, Koren J 3rd, Ghosh S, Blagg BSJ, Blair LJ*, Dickey CA. Hsp90 activator Aha1 drives production of pathological tau aggregates. Proc Natl Acad Sci U S A. 2017 Sep 5;114(36):9707-9712. Epub 2017 Aug 21. https://www.pnas.org/content/114/36/9707.long