Development of GMP-1 a molecular chaperone network modulator protecting mitochondrial function and its assessment in fly and mice models of Alzheimer's disease.

Abstract

Mitochondrial dysfunction is an early feature of Alzheimer's disease (AD) and may play an important role in the pathogenesis of disease. It has been shown that amyloid beta peptide (Aβ) and amyloid precursor protein (APP) interact with mitochondria contributing to the mitochondrial dysfunction in AD. Prevention of abnormal protein targeting to mitochondria can protect normal mitochondrial function, increase neuronal survival and at the end, ameliorate symptoms of AD and other neurodegenerative disorders. First steps of mitochondrial protein import are coordinated by molecular chaperones Hsp70 and Hsp90 that bind to the newly synthesized mitochondria-destined proteins and deliver them to the protein import receptors on the surface of organelle. Here, we have described the development of a novel compound named GMP-1 that disrupts interactions between Hsp70/Hsp90 molecular chaperones and protein import receptor Tom70. GMP-1 treatment of SH-SY5Y cells results in decrease in mitochondria-associated APP and protects SH-SY5Y cells from toxic effect of Aβ1-42 exposure. Experiments in drosophila and mice models of AD demonstrated neuroprotective effect of GMP-1 treatment, improvement in memory and behaviour tests as well as restoration of mitochondrial function.

• Authors: Pavel F Pavlov, Birgit Hutter-Paier, Daniel Havas, Manfred Windisch, Bengt Winblad
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 22 Issue 7 Pg. 3464-3474 (07 2018) ISSN: 1582-4934 [Electronic] England
• PMID: 29704317 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Chemical References

• Amyloid beta-Peptides
• Benzimidazoles
• Glycoproteins
• HSP70 Heat-Shock Proteins
• HSP90 Heat-Shock Proteins
• Mitochondrial Membrane Transport Proteins
• Mitochondrial Precursor Protein Import Complex Proteins
• Molecular Chaperones
• Peptide Fragments
• TOMM34 protein, human
• TOMM70 protein, human
• amyloid beta-protein (1-42)
• tissue-factor-pathway inhibitor 2
• Tacrolimus Binding Proteins
• tacrolimus binding protein 5

Topics

• Alzheimer Disease (drug therapy, metabolism, pathology)
• Amyloid beta-Peptides (genetics)
• Animals
• Animals, Genetically Modified
• Behavior, Animal (drug effects)
• Benzimidazoles (pharmacology, therapeutic use)
• Disease Models, Animal
• Drosophila melanogaster (genetics)
• Glycoproteins (chemistry, genetics, metabolism)
• HSP70 Heat-Shock Proteins (chemistry, metabolism)
• HSP90 Heat-Shock Proteins (chemistry, metabolism)
• Humans
• Mice, Transgenic
• Mitochondria (drug effects, metabolism, pathology)
• Mitochondrial Membrane Transport Proteins (chemistry, genetics, metabolism)
• Mitochondrial Precursor Protein Import Complex Proteins
• Molecular Chaperones (metabolism)
• Molecular Docking Simulation
• Motor Activity (drug effects)
• Peptide Fragments (genetics)
• Tacrolimus Binding Proteins (chemistry, genetics, metabolism)