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Alpha-synuclein supports type 1 interferon signalling in neurons and brain tissue.

Brendan Monogue1,2, Yixi Chen3,4, Hadrian Sparks1

  • 1Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.

Brain : a Journal of Neurology
|July 20, 2022
PubMed
Summary

Alpha-synuclein is crucial for the brain's antiviral defense, supporting neuron-specific interferon responses. This protein aids in activating immune signaling pathways, which is vital for combating viral infections in the central nervous system.

Keywords:
alpha-synucleinbraininterferonneuronvirus

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Area of Science:

  • Neuroimmunology
  • Molecular Neuroscience

Background:

  • Alpha-synuclein is primarily found in neurons and linked to neurodegenerative diseases.
  • Its normal function in neurons, particularly in immune responses, remains unclear.
  • Previous studies suggest a role in the brain's innate immunity.

Purpose of the Study:

  • To elucidate the mechanism by which alpha-synuclein influences neuronal immune responses to viral infections.
  • To investigate the interaction between alpha-synuclein and interferon signaling pathways in neurons.

Main Methods:

  • Utilized alpha-synuclein knockout mice and human dopaminergic neurons challenged with RNA virus.
  • Analyzed the expression of interferon-stimulated genes (ISGs) following viral infection and interferon treatment.
  • Investigated the subcellular localization and interactions of alpha-synuclein and STAT2 using immunofluorescence.
  • Examined brain tissue from viral encephalitis patients for alpha-synuclein modifications.

Main Results:

  • Alpha-synuclein is essential for the induction of interferon-stimulated genes in neurons during viral infection.
  • Neurons lacking alpha-synuclein show impaired responses to type 1 interferon treatment.
  • Alpha-synuclein translocates to the nucleus upon interferon stimulation and is required for STAT2 phosphorylation and activation.
  • Activated STAT2 co-localizes with alpha-synuclein in neurons post-interferon stimulation.
  • Elevated levels of phosphorylated alpha-synuclein were observed in neurons of patients with viral encephalitis.

Conclusions:

  • Alpha-synuclein plays a critical role in supporting neuron-specific interferon responses.
  • The protein acts by localizing to the nucleus, facilitating STAT2 activation, and promoting the expression of interferon-stimulated genes.
  • These findings establish a novel link between interferon signaling and alpha-synuclein function in neuronal immunity.