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

Brendan Monogue; Yixi Chen; Hadrian Sparks; Ranya Behbehani; Andrew Chai; Alexander J Rajic; Aaron Massey; B K Kleinschmidt-Demasters; Matthieu Vermeren; Tilo Kunath; J David Beckham

doi:10.1093/brain/awac192

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

Brain. 2022 Oct 21;145(10):3622-3636. doi: 10.1093/brain/awac192.

Authors

Brendan Monogue^{1

2}, Yixi Chen^{3

4}, Hadrian Sparks¹, Ranya Behbehani³, Andrew Chai³, Alexander J Rajic⁵, Aaron Massey², B K Kleinschmidt-Demasters^{5

6}, Matthieu Vermeren³, Tilo Kunath^{3

4}, J David Beckham^{1

2

5

7}

Affiliations

¹ Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
² Division of Infectious Diseases, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
³ Centre for Regenerative Medicine and the School of Biological Sciences, University of Edinburgh, Edinburgh EH16 4UU, UK.
⁴ UK Centre for Mammalian Synthetic Biology, University of Edinburgh, Edinburgh EH16 4UU, UK.
⁵ Department of Neurology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
⁶ Departments of Pathology and Neurosurgery, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
⁷ Rocky Mountain Regional VA Medical Center, Aurora, CO 80045, USA.

Abstract

The protein alpha-synuclein is predominantly expressed in neurons and is associated with neurodegenerative diseases like Parkinson's disease and dementia with Lewy bodies. However, the normal function of alpha-synuclein in neurons is not clearly defined. We have previously shown that mice lacking alpha-synuclein expression exhibit markedly increased viral growth in the brain, increased mortality and increased neuronal cell death, implicating alpha-synuclein in the neuronal innate immune response. To investigate the mechanism of alpha-synuclein-induced immune responses to viral infections in the brain, we challenged alpha-synuclein knockout mice and human alpha-synuclein knockout dopaminergic neurons with RNA virus infection and discovered that alpha-synuclein is required for neuronal expression of interferon-stimulated genes. Furthermore, human alpha-synuclein knockout neurons treated with type 1 interferon failed to induce a broad range of interferon stimulated genes, implying that alpha-synuclein interacts with type 1 interferon signalling. We next found that alpha-synuclein accumulates in the nucleus of interferon-treated human neurons after interferon treatment and we demonstrated that interferon-mediated phosphorylation of STAT2 is dependent on alpha-synuclein expression in human neurons. Next, we found that activated STAT2 co-localizes with alpha-synuclein following type 1 interferon stimulation in neurons. Finally, we found that brain tissue from patients with viral encephalitis expresses increased levels of phospho-serine129 alpha-synuclein in neurons. Taken together, our results show that alpha-synuclein expression supports neuron-specific interferon responses by localizing to the nucleus, supporting STAT2 activation, co-localizing with phosphorylated STAT2 in neurons and supporting expression of interferon-stimulated genes. These data provide a novel mechanism that links interferon activation and alpha-synuclein function in neurons.

Keywords: alpha-synuclein; brain; interferon; neuron; virus.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Brain* / metabolism
Dopaminergic Neurons* / metabolism
Humans
Interferons* / metabolism
Lewy Bodies / metabolism
Mice
Mice, Knockout
alpha-Synuclein* / metabolism

Substances

alpha-Synuclein
Interferons
SNCA protein, human
Snca protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding