title: Diabetic Risk Factors Promote Islet Amyloid Polypeptide Misfolding by a Common, Membrane-mediated Mechanism.
abstract: The current diabetes epidemic is associated with a diverse set of risk factors including obesity and exposure to plastics. Notably, significant elevations of negatively charged amphiphilic molecules are observed in obesity (e.g. free fatty acids and phosphatidic acid) and plastics exposure (monophthalate esters). It remains unclear whether these factors share pathogenic mechanisms and whether links exist with islet amyloid polypeptide (IAPP) misfolding, a process central to β-cell dysfunction and death. Using a combination of fluorescence, circular dichroism and electron microscopy, we show that phosphatidic acid, oleic acid, and the phthalate metabolite MBzP partition into neutral membranes and enhance IAPP misfolding. The elevation of negative charge density caused by the presence of the risk factor molecules stabilizes a common membrane-bound α-helical intermediate that, in turn, facilitates IAPP misfolding. This shared mechanism points to a critical role for the membrane-bound intermediate in disease pathogenesis, making it a potential target for therapeutic intervention.
authors.affiliation: Department of Biochemistry and Molecular Biology, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, California, USA.
authors.forename: Alan K
authors.initials: AK
authors.lastname: Okada
authors.affiliation: Department of Biochemistry and Molecular Biology, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, California, USA.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Teranishi
authors.affiliation: Department of Biochemistry and Molecular Biology, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, California, USA.
authors.forename: J Mario
authors.initials: JM
authors.lastname: Isas
authors.affiliation: USC Roski Eye Institute, Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
authors.forename: Sahar
authors.initials: S
authors.lastname: Bedrood
authors.affiliation: Department of Physiology and Biophysics, Keck School of Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, California, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Chow
authors.affiliation: Department of Biochemistry and Molecular Biology, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, California, USA.
authors.forename: Ralf
authors.initials: R
authors.lastname: Langen
mesh_terms: D002942:Circular Dichroism; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000378:metabolism*; D008566:Membranes / Q000737:chemistry / Q000378:metabolism*; D008854:Microscopy, Electron; D009765:Obesity / Q000150:complications*; D019301:Oleic Acid / Q000378:metabolism; D061848:Optical Imaging; D010712:Phosphatidic Acids / Q000378:metabolism; D010795:Phthalic Acids / Q000378:metabolism; D017510:Protein Folding
chemical_list: D058228:Islet Amyloid Polypeptide; D010712:Phosphatidic Acids; D010795:Phthalic Acids; D019301:Oleic Acid; C032279:phthalic acid