Neurobiology of Disease: Phosphorylated-tau Associates with HSV-1 Chromatin and Correlates with Nuclear Speckles Decondensation in Low-Density Host Chromatin Regions
Abnormal tau phosphorylation is a key pathophysiological mechanism in neurodegenerative diseases. In addition to genetic and environmental factors, infectious agents, such as Herpes Simplex Virus 1, may be associated with the onset or progression of neurodegenerative diseases, including Alzheimer's disease. However, outstanding questions remain regarding the contribution of viruses in the etiology of neurodegenerative diseases, as viruses may function as risk factors for—as opposed to cause of—neurodegenerative disease. Investigating Herpes Simplex Virus 1 in abnormal tau phosphorylation is important for understanding the role of infectious agents in neurodegeneration.
Investigators including Leonardo D’Aiuto, PhD (Assistant Professor of Psychiatry), Matthew MacDonald, PhD (Associate Professor of Psychiatry), and Vishwajit Nimgaonkar, MD, PhD (Professor of Psychiatry and Human Genetics), from Pitt Psychiatry, generated cellular models of Herpes Simplex Virus 1 acute, latent infection, and viral reactivation from latency in cortical brain organoids. They investigated the interplay between tau phosphorylation and Herpes Simplex Virus 1 infection by employing human induced pluripotent stem cell (iPSC)-derived monolayer neuronal cultures and brain organoids.
Results from the study, published in Neurobiology of Disease, show that Herpes Simplex Virus 1 infection results in the nuclear accumulation of phosphorylated tau in neural precursor cells and neurons, where it binds viral chromatin. Herpes Simplex Virus 1 infection affects the number, the composition and the compactness of nuclear speckles, which are essential for efficient mRNA splicing, paralleling the dysregulation of mRNA splicing observed in Alzheimer's disease. These findings suggest a regulatory role of phosphorylated tau in modulating the viral life cycle and shows that Herpes Simplex Virus 1 infection triggers cellular mechanisms that are commonly observed in Alzheimer's disease.
“Our results provide important insights into how viral infections may influence cellular processes relevant of neurodegenerative conditions, potentially revealing novel targets for therapeutic intervention,” said Dr. D’Aiuto, first and corresponding author of the study.
Phosphorylated-tau associates with HSV-1 chromatin and correlates with nuclear speckles decondensation in low-density host chromatin regions
D’Aiuto L, Caldwell JK, Edwards TG, Zhou C, MacDonald ML, Di Maio R, Joel WA, Hyde VA, Wallace CT, Watkins SC, Wesesky MA, Shemesh OA, Nimgaonkar VL, Bloom DC.
Neurobiology of Disease, Volume 206, 2025, 106804, ISSN 0969-9961, https://doi.org/10.1016/j.nbd.2025.106804.