Pavel Pavlov

Molecular chaperone network and neurodegeneration

Research focus

Development of novel modulators of molecular chaperone network with focus on Alzheimer disease therapy

Most of the neurodegenerative diseases can be classified as proteinopathies or protein misfolding disorders with intra- or extracellular aggregation of certain proteins or peptides observed in affected brain areas. Molecular chaperones are primarily responsible for maintenance of intracellular protein homeostasis including protein folding, transport and degradation. Molecular chaperones as masters of protein homeostasis can be an attractive pharmacological target. However, assuming a long-term therapy for neurodegenerative diseases, the general inhibition or activation of molecular chaperone function can be detrimental. However, we can regulate specific cellular processes avoiding generalized effect on molecular chaperone system by inhibition of protein-protein interactions between molecular chaperones and their particular partner co-chaperones.

Specific goals of the project :

1. Develop potent and specific lead compounds inhibiting particular chaperone-co-chaperone interactions.

2. Generate proof-of-concept biological data supporting our drug development program.

Group leader

Bengt Winblad

Professor, senior

Group members

Supervisor

Pavel Pavlov

Affiliated to research

Postdoc

Lisha Wang

Postdoctoral studies

Affiliated

Rajnish Kumar

Affiliated to research

Selected scientific publications

Small molecule therapeutics for tauopathy in Alzheimer's disease: Walking on the path of most resistance.
Wang L, Bharti , Kumar R, Pavlov PF, Winblad B
Eur J Med Chem 2020 Oct;():112915

Metal Binding by GMP-1 and Its Pyrimido [1, 2]benzimidazole Analogs Confirms Protection Against Amyloid-β Associated Neurotoxicity.
Kumar R, Pavlov PF, Winblad B
J Alzheimers Dis 2020 ;73(2):695-705

In silico identification and biochemical characterization of the human dicarboxylate clamp TPR protein interaction network.
Bernadotte A, Kumar R, Winblad B, Pavlov PF
FEBS Open Bio 2018 Nov;8(11):1830-1843

Development of GMP-1 a molecular chaperone network modulator protecting mitochondrial function and its assessment in fly and mice models of Alzheimer's disease.
Pavlov PF, Hutter-Paier B, Havas D, Windisch M, Winblad B
J Cell Mol Med 2018 07;22(7):3464-3474

Combined x-ray crystallography and computational modeling approach to investigate the Hsp90 C-terminal peptide binding to FKBP51.
Kumar R, Moche M, Winblad B, Pavlov PF
Sci Rep 2017 10;7(1):14288

Mitochondrial dysfunction in a transgenic mouse model expressing human amyloid precursor protein (APP) with the Arctic mutation.
Rönnbäck A, Pavlov PF, Mansory M, Gonze P, Marlière N, Winblad B, et al
J Neurochem 2016 Feb;136(3):497-502

Abnormal platelet amyloid-β protein precursor (AβPP) metabolism in Alzheimer's disease: identification and characterization of a new AβPP isoform as potential biomarker.
Jelic V, Hagman G, Yamamoto NG, Teranishi Y, Nishimura T, Winblad B, et al
J Alzheimers Dis 2013 ;35(2):285-95

Mitochondrial γ-secretase participates in the metabolism of mitochondria-associated amyloid precursor protein.
Pavlov PF, Wiehager B, Sakai J, Frykman S, Behbahani H, Winblad B, et al
FASEB J 2011 Jan;25(1):78-88

Association of Omi/HtrA2 with γ-secretase in mitochondria.
Behbahani H, Pavlov PF, Wiehager B, Nishimura T, Winblad B, Ankarcrona M
Neurochem Int 2010 Nov;57(6):668-75

The amyloid beta-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae.
Hansson Petersen CA, Alikhani N, Behbahani H, Wiehager B, Pavlov PF, Alafuzoff I, et al
Proc Natl Acad Sci U S A 2008 Sep;105(35):13145-50