Open AccessSTING mediates neurodegeneration and neuroinflammation in nigrostriatal α-synucleinopathy
Author(s) -
Jared T. Hinkle,
Jaimin Patel,
Nikhil Panicker,
Senthilkumar S. Karuppagounder,
Devanik Biswas,
Bonn Belingon,
Rong Chen,
Saurav Brahmachari,
Olga Pletniková,
Juan C. Troncoso,
Valina L. Dawson,
Ted M. Dawson
Publication year - 2022
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2118819119
Subject(s) - neurodegeneration , neuroinflammation , substantia nigra , sting , microglia , pars compacta , astrogliosis , dopaminergic , synucleinopathies , parkinson's disease , biology , microbiology and biotechnology , chemistry , neuroscience , immunology , medicine , alpha synuclein , dopamine , pathology , inflammation , central nervous system , disease , engineering , aerospace engineering
Significance It is increasingly recognized that chronic neuroinflammation is causally relevant to neurodegeneration. In Parkinson’s disease (PD), α-synuclein pathology activates inflammatory signaling that disturbs parenchymal homeostasis and disrupts neuron-glia interactions. Herein, we report that the innate immune cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) DNA-sensing pathway is activated in a mouse model of α-synucleinopathy and parkinsonism, leading to type-I interferon activation that precedes the onset of neurodegeneration. Remarkably, STING-deficient mice were protected from dopaminergic neuron loss in this model. We also show that αSyn aggregates can increase STING expression and augment canonical STING activation, suggesting a possible generalized propensity for exaggerated antiviral responses in neurological states with STING elevation. Our results suggest that STING inhibition may be therapeutic in idiopathic PD and possibly other human α-synucleinopathies.