Alpha-synuclein supports type 1 interferon signalling in neurons and brain tissue.
Brendan MonogueYixi ChenHadrian SparksRanya BehbehaniAndrew ChaiAlexander J RajicAaron MasseyB K Kleinschmidt-DemastersMatthieu VermerenTilo KunathJ David BeckhamPublished in: Brain : a journal of neurology (2022)
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.
Keyphrases
- dendritic cells
- spinal cord
- poor prognosis
- cell death
- immune response
- sars cov
- type diabetes
- spinal cord injury
- coronary artery disease
- oxidative stress
- adipose tissue
- risk factors
- dna methylation
- skeletal muscle
- resting state
- toll like receptor
- long non coding rna
- parkinson disease
- deep learning
- multiple sclerosis
- functional connectivity
- cognitive impairment
- small molecule
- inflammatory response
- cardiovascular events
- newly diagnosed
- artificial intelligence
- cardiovascular disease
- deep brain stimulation
- electronic health record
- combination therapy