Perturbations of model membranes induced by pathogenic dynorphin A mutants causing neurodegeneration in human brain |
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Authors: | Madani Fatemeh Taqi Malik Mumtaz Wärmländer Sebastian K T S Verbeek Dineke S Bakalkin Georgy Gräslund Astrid |
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Institution: | aDepartment of Biochemistry and Biophysics, Arrhenius Laboratories for Natural Sciences, Stockholm University, 10691 Stockholm, Sweden;bDepartment of Pharmaceutical Biosciences, Molecular Neuropsychopharmacology, Uppsala University, 751 24 Uppsala, Sweden;cDepartment of Genetics, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands |
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Abstract: | Several effects of the endogenous opioid peptide dynorphin A (Dyn A) are not mediated through the opioid receptors. These effects are generally excitatory, and result in cell loss and induction of chronic pain and paralysis. The mechanism(s) is not well defined but may involve formation of pores in cellular membranes. In the 17-amino acid peptide Dyn A we have recently identified L5S, R6W, and R9C mutations that cause the dominantly inherited neurodegenerative disorder Spinocerebellar ataxia type 23. To gain further insight into non-opioid neurodegenerative mechanism(s), we studied the perturbation effects on lipid bilayers of wild type Dyn A and its mutants in large unilamellar phospholipid vesicles encapsulating the fluorescent dye calcein. The peptides were found to induce calcein leakage from uncharged and negatively charged vesicles to different degrees, thus reflecting different membrane perturbation effects. The mutant Dyn A R6W was the most potent in producing leakage with negatively charged vesicles whereas Dyn A L5S was virtually inactive. The overall correlation between membrane perturbation and neurotoxic response 3] suggests that pathogenic Dyn A actions may be mediated through transient pore formation in lipid domains of the plasma membrane. |
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Keywords: | Prodynorphin Dynorphin A Spinocerebellar ataxia Non-opioid activity Large unilamellar vesicle Calcein leakage |
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