Spike RBD drives sustained Parkinson's disease progression via microglia-neuron crosstalk-mediated RTP801
Sha-Sha Wang1, Ruo-Lan Yuan2, Wen-Fei Wang1
1Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, College of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China; State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Introduction:
Emerging evidence highlights the exacerbation and sustained Parkinson's disease (PD) progression following COVID-19. The SARS-CoV-2 spike receptor-binding domain (RBD), which can persist in the brain post-infection, is a likely contributor, but how it drives this neuropathology is unclear.
Objectives:
To elucidate the underlying mechanisms of long COVID's impact on PD and identify mechanism that contribute to the continuous progression of PD.
Methods:
The SARS-CoV-2 spike RBD was stereotactically injected into the substantia nigra pars compacta of α-synuclein (αSyn) A53T mice within a chronic stress-genetic susceptibility model. We characterized the pathological impact of RBD using motor and non-motor behavioral tests, fMRI-based functional connectivity, in vivo electrophysiology, immunofluorescence, and αSyn aggregate analysis. To elucidate the underlying mechanisms, we then employed RNA-sequencing, transmission electron microscopy, microglial depletion, and comparative studies in αSyn A53T mice lacking RTP801 (αSyn A53T+; RTP801-/-).
Results:
RBD accelerated PD-related motor and non-motor symptom deterioration, impaired brain functional connectivity, and reduced neuronal excitability. It exacerbated dopaminergic neuron degeneration and αSyn aggregation. RTP801 was identified as a critical mediator of RBD-induced PD progression, with its sustained upregulation in dopaminergic neurons dependent on microglial activation. Mechanistically, initially activates microglia induced an increase in neuronal RTP801 via IL-6 and IL-8. RBD leaded to mitochondrial dysfunction, mtDNA release, and activation of the cGAS-STING pathway between neurons and microglia, triggering a mtDNA-cGAS-STING-IFNβ/RTP801 feedback loop, driving neurodegeneration.
Conclusions:
Our findings demonstrate that SARS-CoV-2 RBD exacerbates PD progression through a pathogenic crosstalk between microglia and neurons. This neurotoxic signaling is mediated by a mitochondrial mtDNA-cGAS-STING-IFNβ/RTP801 axis. Targeting RTP801 or the STING pathway may therefore represent a promising therapeutic strategy to mitigate long COVID-associated progression of PD.
Insights
The SARS-CoV-2 spike RBD worsens Parkinson's disease (PD) by activating a harmful feedback loop involving microglia and neurons. Targeting RTP801 or the STING pathway could treat long COVID's impact on PD.
Area of Science:
- Neuroscience
- Immunology
- Virology
Background:
- Emerging evidence links COVID-19 to worsened Parkinson's disease (PD) progression.
- The SARS-CoV-2 spike receptor-binding domain (RBD) may persist in the brain and drive neuropathology, but mechanisms are unclear.
Purpose of the Study:
- To investigate the mechanisms by which SARS-CoV-2 RBD exacerbates PD.
- To identify key pathways contributing to sustained PD progression after COVID-19.
Main Methods:
- Stereotactic injection of SARS-CoV-2 RBD into the substantia nigra of α-synuclein (αSyn) A53T mice.
- Assessment of motor and non-motor behaviors, functional connectivity (fMRI), electrophysiology, and αSyn aggregation.
- Utilized RNA-sequencing, electron microscopy, microglial depletion, and RTP801 knockout models to elucidate mechanisms.
Main Results:
- RBD accelerated PD symptom deterioration, impaired brain connectivity, and reduced neuronal excitability.
- RBD exacerbated dopaminergic neuron loss and αSyn aggregation, with RTP801 identified as a critical mediator.
- A feedback loop involving mitochondrial dysfunction, mtDNA release, microglial activation, and the cGAS-STING-IFNβ/RTP801 axis drove neurodegeneration.
Conclusions:
- SARS-CoV-2 RBD exacerbates PD via pathogenic crosstalk between microglia and neurons.
- A mitochondrial damage-associated molecular pattern (DAMPs)-cGAS-STING-IFNβ/RTP801 axis mediates neurotoxicity.
- Targeting RTP801 or the STING pathway offers potential therapeutic strategies for long COVID-associated PD.
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