Rotenone impairs autophagic flux and lysosomal functions in Parkinson's disease

Neuroscience. 2015 Jan 22;284:900-911. doi: 10.1016/j.neuroscience.2014.11.004. Epub 2014 Nov 13.

Abstract

Background: Rotenone is an environmental neurotoxin that induces accumulation of α-synuclein and degeneration of dopaminergic neurons in substantia nigra pars compacta (SNpc), but the molecular mechanisms are not fully understood. We investigated whether rotenone induced impairment of autophagic flux and lysosomal functions.

Methods: Autophagy flux, accumulation of α-synuclein, lysosomal membrane integrity and neurodegeneration were assessed in the rotenone-treated rat model and PC12 cells, and the effects of the autophagy inducer trehalose on rotenone's cytotoxicity were also studied.

Results: Rotenone administration significantly reduced motor activity and caused a loss of tyrosine hydroxylase in SNpc of Lewis rats. The degeneration of nigral dopaminergic neurons was accompanied by the deposition of α-synuclein aggregates, autophagosomes and redistribution of cathepsin D from lysosomes to the cytosol. In cultured PC12 cells, rotenone also induced increases in protein levels of α-synuclein, microtubule-associated protein 1 light chain 3-II, Beclin 1, and p62. Rotenone increased lysosomal membrane permeability as evidenced by leakage of N-acetyl-beta-d-glucosaminidase and cathepsin D, the effects were blocked by reactive oxygen species scavenger tiron. Autophagy inducer trehalose enhanced the nuclear translocation of transcription factor EB, accelerated the clearance of autophagosomes and α-synuclein and attenuated rotenone-induced cell death of PC12 cells. Meanwhile, administration of trehalose to rats in drinking water (2%) decreased rotenone-induced dopaminergic neurons loss in SNpc.

Conclusions: These studies indicate that the lysosomal dysfunction contributes to rotenone's neurotoxicity and restoration of lysosomal function could be a new therapeutic strategy for Parkinson's disease.

Keywords: Parkinson’s disease; autophagic flux; lysosomal membrane permeability; rotenone; α-synuclein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiparkinson Agents / pharmacology
  • Autophagy / drug effects*
  • Autophagy / physiology
  • Lysosomes / drug effects*
  • Lysosomes / metabolism
  • Male
  • PC12 Cells
  • Parkinsonian Disorders / drug therapy
  • Parkinsonian Disorders / physiopathology*
  • Pars Compacta / drug effects
  • Pars Compacta / physiopathology
  • Random Allocation
  • Rats
  • Rats, Inbred Lew
  • Rotenone / toxicity*
  • Trehalose / pharmacology
  • Tyrosine 3-Monooxygenase / metabolism
  • alpha-Synuclein / metabolism

Substances

  • Antiparkinson Agents
  • Snca protein, rat
  • alpha-Synuclein
  • Rotenone
  • Trehalose
  • Tyrosine 3-Monooxygenase