title: Impaired autophagic flux is critically involved in drug-induced dopaminergic neuronal death.
abstract: Autophagy is an evolutionarily conserved process that mediates the degradation of abnormal proteins and the removal of dysfunctional organelles. Recently, accumulating evidence has implicated the dysregulation of autophagy as underlying the pathophysiology of several neurodegenerative diseases. Using culture models of Parkinson's disease, we have investigated whether and how prototypic autophagic events occur upon exposure to N-methyl-4-phenylpyridinium, a dopaminergic neurotoxin, or nigericin, a K(+)/H(+) ionophore. From these independent studies, we have found that these drugs equally induce morphological and biochemical changes typical of autophagy, including accumulation of autophagic vacuoles, appearance of LC3-II forms, and alteration in the expression and distribution of p62. Further investigation has indicated that drug-induced autophagic phenomena are largely the consequences of an impaired autophagic flux. In these cell death paradigms, we have intriguingly found that Bak, a prototypic proapoptotic protein of the Bcl-2 family, exerts a protective role via reduction of the area occupied by swollen vacuoles and appearance of the LC3-II form, whereas silencing of Bak aggravates these phenomena. Further study has indicated that a protective role for Bak is primarily ascribed to its regulatory effect on the maintenance of autophagic flux and vacuole homeostasis. In this regard, a regulatory role for calcium has been proposed.
authors.affiliation: Department of Biology Yonsei University College of Life Science and Biotechnology, Seoul 120-749, South Korea.
authors.forename: Junghyun
authors.initials: J
authors.lastname: Lim
authors.forename: Yunsu
authors.initials: Y
authors.lastname: Lee
authors.forename: Shinae
authors.initials: S
authors.lastname: Jung
authors.forename: Moussa B H
authors.initials: MB
authors.lastname: Youdim
authors.forename: Young J
authors.initials: YJ
authors.lastname: Oh
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology*; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D002461:Cell Line, Transformed; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D006801:Humans; D007476:Ionophores / Q000494:pharmacology; D046529:Microscopy, Electron, Transmission; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009498:Neurotoxins / Q000494:pharmacology*; D009550:Nigericin / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012402:Rotenone / Q000031:analogs & derivatives / Q000494:pharmacology; D000071456:Sequestosome-1 Protein; D013997:Time Factors; D014162:Transfection; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D007476:Ionophores; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D009498:Neurotoxins; D019253:Proto-Oncogene Proteins c-bcl-2; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D012402:Rotenone; C028404:rotenolone; D014446:Tyrosine 3-Monooxygenase; D015655:1-Methyl-4-phenylpyridinium; D009550:Nigericin
keywords: Autophagic flux; Bak; MPP+; Neurodegeneration; Nigericin