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  3. Proteomic Analysis of Endemic Viral Infections in Neurons offers Insights into Neurodegenerative Diseases

Proteomic Analysis of Endemic Viral Infections in Neurons offers Insights into Neurodegenerative Diseases

  • bioRxiv. 2025 Mar 17:2025.03.17.643709. doi: 10.1101/2025.03.17.643709.
Ziyi Li 1 2 3,  Negin P Martin 4 3,  Jacob Epstein 1,  Shih-Heng Chen 4,  Ying Hao 1,  Daniel M Ramos 1,  Kate M Andersh 1,  Paige Jarreau 1,  Cory Weller 1 2,  Mike A Nalls 1 2,  Caroline B Pantazis 1,  Luigi Ferrucci 5,  Mark R Cookson 6,  Andrew B Singleton 1 6,  Yue Andy Qi 1 7,  Jerrel L Yakel 4
Affiliations

Affiliations

  • 1 Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
  • 2 DataTecnica LLC, Washington, DC 20812, USA.
  • 3 These authors contributed equally.
  • 4 Neurobiology Laboratory, National Institute of Environmental Health Sciences.
  • 5 Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, USA.
  • 6 Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
  • 7 Lead contact.
PMID: 40166347 DOI: 10.1101/2025.03.17.643709
Abstract

Endemic viral infections with low pathogenicity are often overlooked due to their mild symptoms, yet they can exert long-term effects on cellular function and contribute to disease pathogenesis. While viral infections have been implicated in neurodegenerative disorders, their impact on the neuronal proteome remains poorly understood. Here, we differentiated human induced pluripotent stem cells (KOLF2.1J) into mature neurons to investigate virus-induced proteomic changes following Infection with five neurotropic endemic human viruses: Herpes simplex virus 1 (HSV-1), Human coronavirus 229E (HCoV-229E), Epstein-Barr virus (EBV), Varicella-Zoster virus (VZV), and Influenza A virus (H1N1). Given that these viruses can infect adults and have the potential to cross the placental barrier, their molecular impact on neurons may be relevant across the lifespan. Using mass spectrometry-based proteomics with a customized library for simultaneous detection of human and Viral Proteins, we confirmed successful infections and identified virus-specific proteomic signatures. Notably, virus-induced protein expression changes converged on key neuronal pathways, including those associated with neurodegeneration. Gene co-expression network analysis identified protein modules correlated with Viral Proteins. Pathway enrichment analysis of these modules revealed associations with the nervous system, including pathways linked to Alzheimer's and Parkinson's disease. Remarkably, several viral-induced proteomic alterations overlapped with changes observed in postmortem Alzheimer's patient brains, suggesting a mechanistic connection between viral exposure and neurodegenerative disease progression. These findings provide molecular insights into how common viral infections perturb neuronal homeostasis and may contribute to neurodegenerative pathology, highlighting the need to consider endemic viruses as potential environmental risk factors in neurological disorders.

Keywords

Alzheimer’s; KOLF2.1J; Neurodegeneration; Neuroinflammation; Neurons; Proteomics; Virus.

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