The STING pathway drives noninflammatory neurodegeneration in NGLY1 deficiency

  • J Exp Med. 2025 Oct 6;222(10):e20242296. doi: 10.1084/jem.20242296.
Kun Yang  1 ,  Gustavo Torres-Ramirez  1 ,  Nicole Dobbs  1 ,  Jie Han  1 ,  Makoto Asahina  2 ,  Reiko Fujinawa  3  2 ,  Kun Song  1 ,  Yun Liu  4 ,  Weichun Lin  4 ,  Angelica Oviedo  5 ,  Chuo Chen  6 ,  Lei Zhu  7 ,  William F Mueller  7 ,  Kevin Lee  8 ,  Tadashi Suzuki  3  2 ,  Nan Yan  1
Affiliations
  • 1. Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 2. Takeda-CiRA Joint Program (T-CiRA) , Kanagawa, Japan.
  • 3. Glycometabolic Biochemistry Laboratory, RIKEN Pioneering Research Institute, Saitama, Japan.
  • 4. Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 5. Pathology and Laboratory Medicine, Burrell College of Osteopathic Medicine, Las Cruces, NM, USA.
  • 6. Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 7. Grace Science, LLC , Menlo Park, CA, USA.
  • 8. Grace Science Foundation , Menlo Park, CA, USA.
PMID: 40644312 DOI: 10.1084/jem.20242296
Abstract

The STING pathway is increasingly recognized as a key regulator of neuroinflammation in neurodegenerative disease, but its role in noninflammatory conditions remains unclear. We generated a postnatal inducible whole-body Ngly1 knockout mouse (iNgly1-/-) to model NGLY1 deficiency, an early-onset neurodegenerative disorder. iNgly1-/- mice exhibit progressive motor deficits, Purkinje cell loss, and shortened lifespan without evidence of gliosis or immune activation. Cell type-specific deletion of Ngly1 in Purkinje cells or microglia failed to induce disease, suggesting multiple cell-intrinsic and cell-extrinsic signals are required. Genetic ablation of Sting1 in iNgly1-/- mice rescues Purkinje cell loss, improves motor function, and extends lifespan. Single-nucleus RNA Sequencing reveals proteostasis disruption in Purkinje cells, altered cerebellar granule cell subpopulations, and STING-dependent suppression of Cholesterol biosynthesis in glia. Pharmacological inhibition of STING with an orally bioactive antagonist, VS-X4, significantly mitigates neuropathology and motor disease. These findings identify STING as a key mediator of neuropathology in NGLY1 deficiency and implicate a role of STING in noninflammatory Neurological Disease.

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