Maria Rosalia Mangione1, Silvia Vilasi2, Claudia Marino3, Fabio Librizzi1, Claudio Canale4, Dario Spigolon5, Fabio Bucchieri6, Alberto Fucarino7, Rosa Passantino1, Francesco Cappello8, Donatella Bulone1, Pier Luigi San Biagio1. 1. Institute of Biophysics, National Research Council, Palermo, Italy. 2. Institute of Biophysics, National Research Council, Palermo, Italy. Electronic address: silvia.vilasi@pa.ibf.cnr.it. 3. Institute of Biophysics, National Research Council, Palermo, Italy; Department of Neurology, University of Texas Medical Branch, Galveston, TX, USA; Department of Experimental Biomedicine and Clinical Neurosciences, University of Palermo, Italy. 4. Nanophysics Department, Istituto Italiano di Tecnologia, Italy. 5. Institute of Biophysics, National Research Council, Palermo, Italy; Department of Physics and Chemistry, University of Palermo, Palermo, Italy. 6. Department of Experimental Biomedicine and Clinical Neurosciences, University of Palermo, Italy; Institute of Biomedicine and Molecular Immunology, National Research Council, Palermo, Italy; Euro-Mediterranean Institute of Science and Technology, Palermo, Italy. 7. Department of Experimental Biomedicine and Clinical Neurosciences, University of Palermo, Italy; Euro-Mediterranean Institute of Science and Technology, Palermo, Italy. 8. Institute of Biophysics, National Research Council, Palermo, Italy; Department of Experimental Biomedicine and Clinical Neurosciences, University of Palermo, Italy; Euro-Mediterranean Institute of Science and Technology, Palermo, Italy.
Abstract
BACKGROUND: Molecular chaperones are a very special class of proteins that play essential roles in many cellular processes like folding, targeting and transport of proteins. Moreover, recent evidence indicates that chaperones can act as potentially strong suppressor agents in Alzheimer's disease (AD). Indeed, in vitro experiments demonstrate that several chaperones are able to significantly slow down or suppress aggregation of Aβ peptide and in vivo studies reveal that treatment with specific chaperones or their overexpression can ameliorate some distinct pathological signs characterizing AD. METHODS: Here we investigate using a biophysical approach (fluorescence, circular dichroism (CD), transmission electron (TEM) and atomic force (AFM) microscopy, size exclusion chromatography (SEC)) the effect of the human chaperonin Hsp60 on Aβ fibrillogenesis. RESULTS: We found that Hsp60 powerfully inhibits Aβ amyloid aggregation, by closing molecular pathways leading to peptide fibrillogenesis. CONCLUSIONS: We observe that Hsp60 inhibits Aβ aggregation through a more complex mechanism than a simple folding chaperone action. The action is specifically directed toward the early oligomeric species behaving as aggregation seeds for on-pathway amyloid fibrillogenesis. GENERAL SIGNIFICANCE: Understanding the specificity of the molecular interactions of Hsp60 with amyloid Aβ peptide allowed us to emphasize the important aspects to be taken into consideration when considering the recent promising therapeutic strategies for neurodegeneration.
BACKGROUND: Molecular chaperones are a very special class of proteins that play essential roles in many cellular processes like folding, targeting and transport of proteins. Moreover, recent evidence indicates that chaperones can act as potentially strong suppressor agents in Alzheimer's disease (AD). Indeed, in vitro experiments demonstrate that several chaperones are able to significantly slow down or suppress aggregation of Aβ peptide and in vivo studies reveal that treatment with specific chaperones or their overexpression can ameliorate some distinct pathological signs characterizing AD. METHODS: Here we investigate using a biophysical approach (fluorescence, circular dichroism (CD), transmission electron (TEM) and atomic force (AFM) microscopy, size exclusion chromatography (SEC)) the effect of the human chaperonin Hsp60 on Aβ fibrillogenesis. RESULTS: We found that Hsp60 powerfully inhibits Aβ amyloid aggregation, by closing molecular pathways leading to peptide fibrillogenesis. CONCLUSIONS: We observe that Hsp60 inhibits Aβ aggregation through a more complex mechanism than a simple folding chaperone action. The action is specifically directed toward the early oligomeric species behaving as aggregation seeds for on-pathway amyloid fibrillogenesis. GENERAL SIGNIFICANCE: Understanding the specificity of the molecular interactions of Hsp60 with amyloid Aβ peptide allowed us to emphasize the important aspects to be taken into consideration when considering the recent promising therapeutic strategies for neurodegeneration.
Authors: Bhuvaneswari Kannaian; Bhargy Sharma; Margaret Phillips; Anup Chowdhury; Malathy S S Manimekalai; Sunil S Adav; Justin T Y Ng; Ambrish Kumar; Sierin Lim; Yuguang Mu; Siu K Sze; Gerhard Grüber; Konstantin Pervushin Journal: Sci Rep Date: 2019-08-29 Impact factor: 4.379
Authors: Indumathi Krishnan-Sivadoss; Iván A Mijares-Rojas; Ramiro A Villarreal-Leal; Guillermo Torre-Amione; Anne A Knowlton; C Enrique Guerrero-Beltrán Journal: Med Res Rev Date: 2020-08-17 Impact factor: 12.388