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Oral Administration of Rotenone using a Gavage and Image Analysis of Alpha-synuclein Inclusions in the Enteric Nervous System
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Oral Administration of Rotenone using a Gavage and Image Analysis of Alpha-synuclein Inclusions in the Enteric Nervous System

Published on: October 26, 2010

Rotenone upregulates alpha-synuclein and myocyte enhancer factor 2D independently from lysosomal degradation

Gessica Sala1, Alessandro Arosio, Giovanni Stefanoni

  • 1Laboratory of Neurobiology, Department of Surgery and Interdisciplinary Medicine, University of Milano-Bicocca, Via Cadore 48, 20900 Monza, Italy. gessica.sala@unimib.it

Biomed Research International
|August 29, 2013
PubMed

Insights

Parkinson's disease involves chaperone-mediated autophagy (CMA) dysfunction. Rotenone increases alpha-synuclein and MEF2D by stimulating synthesis, not inhibiting CMA degradation, unlike ammonium chloride.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Biochemistry

Background:

  • Chaperone-mediated autophagy (CMA) is crucial for degrading alpha-synuclein, a protein implicated in Parkinson's disease (PD) pathogenesis.
  • The impact of PD-related toxins on CMA remains incompletely understood.

Purpose of the Study:

  • To investigate the effect of rotenone, a mitochondrial complex I inhibitor, on CMA substrates (alpha-synuclein, MEF2D) and effectors (lamp2A, hsc70) in a human dopaminergic cell line.
  • To compare rotenone's effects with those of lysosome inhibition by ammonium chloride.

Main Methods:

  • Utilized a human dopaminergic neuroblastoma SH-SY5Y cell line.
  • Administered rotenone and ammonium chloride to cells.
  • Quantified protein levels of alpha-synuclein, MEF2D, lamp2A, and hsc70.
  • Assessed protein synthesis, degradation, and nuclear translocation.

Main Results:

  • Rotenone upregulated alpha-synuclein and MEF2D protein levels by stimulating de novo synthesis, independent of CMA-mediated degradation.
  • Increased MEF2D transcription and nuclear levels under rotenone treatment conferred protection against mitochondrial dysfunction and oxidative stress.
  • Ammonium chloride induced cytosolic accumulation of alpha-synuclein and MEF2D by inhibiting lysosomal degradation and decreased MEF2D nuclear levels by downregulating transcription.

Conclusions:

  • Rotenone influences alpha-synuclein and MEF2D protein levels through a mechanism distinct from lysosomal degradation inhibition.
  • MEF2D's transcriptional upregulation and nuclear localization under rotenone exposure may offer a protective cellular response.
  • Understanding toxin-specific effects on CMA pathways is vital for elucidating Parkinson's disease mechanisms.

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