Abstract
Carnosine, a common dipeptide in mammals, has previously been shown to dissemble alpha-crystallin amyloid fibrils. To date, the dipeptide's anti-fibrillogensis effect has not been thoroughly characterized in other proteins. For a more complete understanding of carnosine's mechanism of action in amyloid fibril inhibition, we have investigated the effect of the dipeptide on lysozyme fibril formation and induced cytotoxicity in human neuroblastoma SH-SY5Y cells. Our study demonstrates a positive correlation between the concentration and inhibitory effect of carnosine against lysozyme fibril formation. Molecular docking results show carnosine's mechanism of fibrillogenesis inhibition may be initiated by binding with the aggregation-prone region of the protein. The dipeptide attenuates the amyloid fibril-induced cytotoxicity of human neuronal cells by reducing both apoptotic and necrotic cell deaths. Our study provides solid support for carnosine's amyloid fibril inhibitory property and its effect against fibril-induced cytotoxicity in SH-SY5Y cells. The additional insights gained herein may pave way to the discovery of other small molecules that may exert similar effects against amyloid fibril formation and its associated neurodegenerative diseases.
Highlights
Amyloid diseases, including hemodialysis amyloidosis, type II diabetes, Parkinson’s disease, transmissible spongiform encephalopathies, Huntington’s disease, and Alzheimer’s disease, are a group of human diseases that are characterized by the formation of extracellular insoluble aggregates or deposits in certain tissues and organs [1,2,3,4]
We thoroughly examined the dose-dependent effect of carnosine on Hen egg-white lysozyme (HEWL) fibril formation from the protein structural level via a wide variety of methods, including several spectroscopic techniques (e.g., thioflavin T fluorescence spectroscopy, Congo red absorption spectroscopy, far-UV circular dichroism (CD) spectroscopy, and Nile red fluorescence spectroscopy) and transmission electron microscopy (TEM)
HEWL fibrillogenesis was affected by carnosine as revealed by thioflavin T (ThT) fluorescence and Congo red binding
Summary
Amyloid diseases, including hemodialysis amyloidosis, type II (or noninsulin-dependent) diabetes, Parkinson’s disease, transmissible spongiform encephalopathies, Huntington’s disease, and Alzheimer’s disease, are a group of human diseases that are characterized by the formation of extracellular insoluble aggregates or deposits ( termed as amyloid fibrils) in certain tissues and organs [1,2,3,4]. While the precursor proteins involved in the aforesaid diseases share no sequence homology and native structural motif similarity, they form fibrillar aggregates with common morphological and histochemical features. The formation of amyloid fibrils or fibril-like aggregates has been observed in proteins that are not associated with any form of disease under certain environmental stresses (e.g., high temperature, extreme pH, vigorous agitation, and high pressure) [7,8,9]. Evidence has shown that the morphological, histochemical, and cytotoxic properties of the aggregates derived from these nondisease-related proteins are similar to those of disease-associated amyloid proteins, suggesting that amyloidogenicity or amyloid fibril-forming propensity is a generic property of all polypeptides [10,11]. Hen eggwhite lysozyme serves as a nice model system with which to study in vitro phenomena associated with fibril formation
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