Impaired autophagic flux is critically involved in drug-induced dopaminergic neuronal death

Junghyun Lim, Yunsu Lee, Shinae Jung, Moussa B.H. Youdim, Young J. Oh

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)S162-S166
JournalParkinsonism and Related Disorders
Volume20
Issue numberSUPPL.1
DOIs
Publication statusPublished - 2014 Jan 1

All Science Journal Classification (ASJC) codes

  • Neurology
  • Geriatrics and Gerontology
  • Clinical Neurology

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