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The Interaction between Amyloid Prefibrillar Oligomers of Salmon Calcitonin and a Lipid-Raft Model: Molecular Mechanisms Leading to Membrane Damage, Ca2+-Influx and Neurotoxicity

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Centro Nazionale Malattie Rare, Istituto Superiore di Sanità, I-00161 Roma, Italy
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CNR-Istituto per i Sistemi Biologici, UOS di Roma, c/o Dipartimento di Chimica, Sapienza Università di Roma, I-00185 Roma, Italy
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Dipartimento di Fisica e Scienze Chimiche, Università dell’Aquila, via Vetoio (Coppito 1), 67010 L’Aquila, Italy
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Dipartimento di Chimica, Sapienza Università di Roma, I-00185 Roma, Italy
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Centro Grandi Strumentazioni e Core Facilities, Istituto Superiore di Sanità, I-00161 Roma, Italy
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Grupo Productos Naturales Marinos, Facultad de Ciencias Farmacéuticas y Alimentarias, Instituto de Física, Universidad de Antioquia, Calle 70 No. 52-21, Medellín 050010, Colombia
*
Author to whom correspondence should be addressed.
Biomolecules 2020, 10(1), 58; https://doi.org/10.3390/biom10010058
Received: 6 November 2019 / Revised: 19 December 2019 / Accepted: 27 December 2019 / Published: 29 December 2019
(This article belongs to the Section Biomacromolecules)
To investigate the interaction between amyloid assemblies and “lipid-rafts”, we performed functional and structural experiments on salmon calcitonin (sCT) solutions rich in prefibrillar oligomers, proto- and mature-fibers interacting with liposomes made of monosialoganglioside-GM1 (4%), DPPC (48%) and cholesterol (48%). To focus on the role played by electrostatic forces and considering that sCT is positive and GM1 is negative at physiologic pH, we compared results with those relative to GM1-free liposomes while, to assess membrane fluidity effects, with those relative to cholesterol-free liposomes. We investigated functional effects by evaluating Ca2+-influx in liposomes and viability of HT22-DIFF neurons. Only neurotoxic solutions rich in unstructured prefibrillar oligomers were able to induce Ca2+-influx in the “lipid-rafts” model, suggesting that the two phenomena were correlated. Thus, we investigated protein conformation and membrane modifications occurring during the interaction: circular dichroism showed that “lipid-rafts” fostered the formation of β-structures and energy filtered-transmission electron microscopy that prefibrillar oligomers formed pores, similar to Aβ did. We speculate that electrostatic forces between the positive prefibrillar oligomers and the negative GM1 drive the initial binding while the hydrophobic profile and flexibility of prefibrillar oligomers, together with the membrane fluidity, are responsible for the subsequent pore formation leading to Ca2+-influx and neurotoxicity. View Full-Text
Keywords: amyloid proteins; neurotoxicity; lipid-rafts; GM1; cholesterol; salmon calcitonin; circular dichroism; transmission electron microscopy; ca2+-influx amyloid proteins; neurotoxicity; lipid-rafts; GM1; cholesterol; salmon calcitonin; circular dichroism; transmission electron microscopy; ca2+-influx
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Diociaiuti, M.; Bombelli, C.; Zanetti-Polzi, L.; Belfiore, M.; Fioravanti, R.; Macchia, G.; Giordani, C. The Interaction between Amyloid Prefibrillar Oligomers of Salmon Calcitonin and a Lipid-Raft Model: Molecular Mechanisms Leading to Membrane Damage, Ca2+-Influx and Neurotoxicity. Biomolecules 2020, 10, 58.

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