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Studying Pre-formed Fibril Induced α-Synuclein Accumulation in Primary Embryonic Mouse Midbrain Dopamine Neurons
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Limited effects of dysfunctional macroautophagy on the accumulation of extracellularly derived α-synuclein in

Lisa Fellner1, Edith Buchinger2, Dominik Brueck2

  • 1Department of Neurology, Medical University of Innsbruck, Innrain 66, G2, 6020, Innsbruck, Austria. lisa.fellner@i-med.ac.at.

BMC Neuroscience
|May 23, 2018
PubMed
Abstract

Insights

Dysfunctional macroautophagy does not worsen α-synuclein buildup in brain cells, but may increase oxidative stress. Multiple pathways likely contribute to glial cytoplasmic inclusions in multiple system atrophy.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Biochemistry

Background:

  • Multiple system atrophy (MSA) is a neurodegenerative disorder.
  • Glial cytoplasmic inclusions (GCIs) composed of α-synuclein are a hallmark of MSA.
  • The exact mechanisms driving GCI formation remain unclear, with potential roles for α-synuclein uptake, overexpression, and impaired protein degradation.

Purpose of the Study:

  • To investigate if impaired macroautophagy exacerbates the accumulation of extracellular α-synuclein within oligodendroglia.
  • To explore the relationship between macroautophagy dysfunction and the formation of GCIs in MSA.

Main Methods:

  • Oligodendroglia were exposed to monomeric and fibrillar extracellular α-synuclein.
  • Macroautophagy was inhibited using bafilomycin A1 or genetic knockdown of LC3B.
  • Confocal microscopy was used to assess GCI-like formation and α-synuclein levels.

Main Results:

  • Oligodendroglia demonstrated the capacity to internalize both monomeric and fibrillar forms of extracellular α-synuclein.
  • Inhibition of macroautophagy did not significantly alter the levels of internalized α-synuclein.
  • Blocking macroautophagy led to increased oxidative stress, particularly when cells were treated with fibrillar α-synuclein.

Conclusions:

  • Isolated macroautophagy dysfunction is insufficient to promote the abnormal accumulation of internalized α-synuclein in vitro.
  • Impaired macroautophagy may contribute to oxidative stress in the context of fibrillar α-synuclein.
  • The formation of GCIs in MSA likely involves multiple synergistic pathways beyond macroautophagy dysfunction.
Keywords:
Glial cytoplasmic inclusionsMacroautophagyMultiple system atrophyOligodendrogliaα-Synuclein

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