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Mutant SOD1 inhibits ER-Golgi transport in amyotrophic lateral sclerosis

Julie D Atkin1, Manal A Farg, Kai Ying Soo

  • 1Department of Biochemistry, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Melbourne, Australia; Department of Florey Neuroscience, University of Melbourne, Parkville, Melbourne, Australia.

Journal of Neurochemistry
|October 19, 2013
PubMed

Insights

Misfolded mutant superoxide dismutase (mSOD1) in ALS inhibits ER-Golgi transport, preceding cellular damage. Restoring this transport pathway protects against neurodegeneration.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Molecular Biology

Background:

  • Amyotrophic lateral sclerosis (ALS) is linked to misfolded Cu/Zn-superoxide dismutase (mSOD1).
  • The precise mechanisms by which mSOD1 triggers cellular pathology, including endoplasmic reticulum (ER) stress, remain incompletely understood.

Purpose of the Study:

  • To elucidate the early cellular events initiated by mSOD1 expression in ALS.
  • To investigate the role of ER-Golgi transport in mSOD1-mediated neurotoxicity.

Main Methods:

  • Cellular localization studies of mSOD1 in neuronal cells.
  • Assays to measure secretory protein transport from the ER to the Golgi apparatus.
  • Analysis of ER stress, Golgi fragmentation, protein aggregation, and apoptosis in mSOD1-expressing cells.
  • Functional rescue experiments overexpressing Sar1, a key component of ER-Golgi transport.

Main Results:

  • Mutant SOD1 (mSOD1) was found predominantly in the cytoplasm of neuronal cells.
  • mSOD1 significantly inhibited secretory protein transport from the ER to the Golgi apparatus.
  • Inhibition of ER-Golgi trafficking preceded ER stress, Golgi fragmentation, protein aggregation, and apoptosis.
  • Overexpression of Sar1 restored ER-Golgi transport, protected against inclusion formation, and reduced apoptosis.

Conclusions:

  • Dysfunction in ER-Golgi transport is an early pathogenic event in cells expressing mSOD1.
  • Impaired ER-Golgi trafficking links several key cellular pathologies observed in ALS.
  • Targeting ER-Golgi transport may offer a therapeutic strategy for ALS.
Keywords:
ER-Golgi transportamyotrophic lateral sclerosisneurodegeneration

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