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

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

doi:10.1093/brain/awac192

Cited by 24 publications

(21 citation statements)

References 44 publications

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“…Beatman et al 34 documented that native neuronal expression of αSyn inhibited viral infection in the central nervous system, while virusinduced increased αSyn expression localized to endoplasmic reticulum-derived membranes, modulated virus-induced endoplasmic reticulum stress signaling, and inhibited viral replication, growth, and injury in the CNS. Similarly, another study evidenced that αSyn is required for neuronal expression of interferonstimulated genes and supports neuron-specific interferon responses 35 . Together, these findings suggest a prominent role of αSyn protein, as well as virus-induced increased expression of αSyn, in mediating antiviral responses to CNS infections.…”

Section: Discussionmentioning

confidence: 93%

Detection of SARS-CoV-2 viral proteins and genomic sequences in human brainstem nuclei

Emmi

Rizzo

Barzon

et al. 2023

npj Parkinsons Dis.

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Neurological manifestations are common in COVID-19, the disease caused by SARS-CoV-2. Despite reports of SARS-CoV-2 detection in the brain and cerebrospinal fluid of COVID-19 patients, it is still unclear whether the virus can infect the central nervous system, and which neuropathological alterations can be ascribed to viral tropism, rather than immune-mediated mechanisms. Here, we assess neuropathological alterations in 24 COVID-19 patients and 18 matched controls who died due to pneumonia/respiratory failure. Aside from a wide spectrum of neuropathological alterations, SARS-CoV-2-immunoreactive neurons were detected in the dorsal medulla and in the substantia nigra of five COVID-19 subjects. Viral RNA was also detected by real-time RT-PCR. Quantification of reactive microglia revealed an anatomically segregated pattern of inflammation within affected brainstem regions, and was higher when compared to controls. While the results of this study support the neuroinvasive potential of SARS-CoV-2 and characterize the role of brainstem inflammation in COVID-19, its potential implications for neurodegeneration, especially in Parkinson’s disease, require further investigations.

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Section: Discussionmentioning

confidence: 93%

Detection of SARS-CoV-2 viral proteins and genomic sequences in human brainstem nuclei

Emmi

Rizzo

Barzon

et al. 2023

npj Parkinsons Dis.

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“…Based on our results, STAT2 could be involved in microglial activation by increasing the expression of MHC II and pro-inflammatory factors, contributing to the pathogenesis of neuropathic pain. However, considering that the expression of STAT2 was also observed in a small portion of neurons in the SDH, the role of neuronal STAT2 in neuropathic pain could not be ruled out as a recent study indicates that STAT2 is also involved in the neuronal innate immune response ( Monogue et al, 2022 ). Further studies are still needed to explore the cell-specific role of STAT2 in the pathogenesis of neuropathic pain.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of nuclear STAT2 protein in the spinal dorsal horn is involved in neuropathic pain following chronic constriction injury of the rat sciatic nerve

Huang

Ding

et al. 2023

Front. Pharmacol.

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Regulation of gene transcription in the spinal dorsal horn (SDH) plays a critical role in the pathophysiology of neuropathic pain. In this study, we investigated whether the transcription factor STAT2 affects neuropathic pain and evaluated its possible mechanisms. A proteomic analysis showed that the nuclear fraction of STAT2 protein in the SDH was downregulated after chronic constriction injury of the rat sciatic nerve, which was associated with the development of neuropathic pain. Similarly, siRNA-induced downregulation of STAT2 in the SDH of naïve rats also resulted in pain hypersensitivity. Using RNA-sequencing analysis, we showed that reduction of nuclear STAT2 after chronic constriction injury was associated with increased expression of microglial activation markers, including the class II transactivator and major histocompatibility complex class II proteins. In addition, siRNA-induced downregulation of STAT2 promoted microglial activation and pro-inflammatory cytokine expression in the SDH. Taken together, these results showed that chronic constriction injury caused downregulation of nuclear STAT2 in the SDH, which may result in microglial activation and development of neuropathic pain. Our findings indicate that restoration of nuclear expression of STAT2 could be a potential pathway for the treatment of neuropathic pain.

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“…aSyn, tau, Aβ) would serve as a failsafe. Notably, the sterile enhancement of microglial IFN-I cascades has been previously shown (34,49,62,63) indicating that their enhancement in the setting of SARS-CoV-2 (61, 65) infections may require proteins or DAMPs rather than a complete virion-a concept that would account for the persistence of neuroinflammation past virus clearance (59).…”

Section: Sars-cov-associated Neurocognitive Disorder As Innate Immuni...mentioning

confidence: 98%

“…An example of this proposed mechanism can be found in the amyloidogenic interaction between N and alpha-synuclein (aSyn), where N functions as a scaffold for aSyn aggregation ( 61 ). The abrogation of aSyn would arrest its function as a canonical, neuron-specific IFN-I modulator ( 62 ); the aggregation of aSyn however would in turn activate IFN-I by a (presumably) non-canonical pathway, observed in neurodegenerative disease ( 63 ). This sterile proinflammatory signal could be relayed centrally from infected microvascular endothelia or olfactory epithelial cells, to be intercepted primarily by microglia ( 7 , 11 , 57 ).…”

Section: The Viral Lifecycle: Kinase Recruitment and Tauopathymentioning

confidence: 99%

Type I interferon signaling in SARS-CoV-2 associated neurocognitive disorder (SAND): Mapping host-virus interactions to an etiopathogenesis

2022

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Epidemiological, clinical, and radiological studies have provided insights into the phenomenology and biological basis of cognitive impairment in COVID-19 survivors. Furthermore, its association with biomarkers associated with neuroinflammation and neurodegeneration supports the notion that it is a distinct aspect of LongCOVID syndrome with specific underlying biology. Accounting for the latter, translational studies on SARS-CoV-2's interactions with its hosts have provided evidence on type I interferon dysregulation, which is seen in neuroinflammatory and neurodegenerative diseases. To date, studies attempting to describe this overlap have only described common mechanisms. In this manuscript, we attempt to propose a mechanistic model based on the host-virus interaction hypothesis. We discuss the molecular basis for a SARS-CoV-2-associated neurocognitive disorder (SAND) focusing on specific genes and pathways with potential mechanistic implications, several of which have been predicted by Vavougios and their research group. Furthermore, our hypothesis links translational evidence on interferon-responsive gene perturbations introduced by SARS-CoV-2 and known dysregulated pathways in dementia. Discussion emphasizes the crosstalk between central and peripheral immunity via danger-associated molecular patterns in inducing SAND's emergence in the absence of neuroinfection. Finally, we outline approaches to identifying targets that are both testable and druggable, and could serve in the design of future clinical and translational studies.

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

Cited by 24 publications

References 44 publications

Detection of SARS-CoV-2 viral proteins and genomic sequences in human brainstem nuclei

Detection of SARS-CoV-2 viral proteins and genomic sequences in human brainstem nuclei

Downregulation of nuclear STAT2 protein in the spinal dorsal horn is involved in neuropathic pain following chronic constriction injury of the rat sciatic nerve

Type I interferon signaling in SARS-CoV-2 associated neurocognitive disorder (SAND): Mapping host-virus interactions to an etiopathogenesis

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