Zika virus impairs non-homologous end joining and exacerbates DNA damage in neural progenitors derived from Huntington’s disease iPSCs via mutant huntingtin-elicited Ku70/Ku80 complex disruption

• Published in: Stem Cell Research & Therapy
• Main Authors: Feng-Lan Chiu, Jian-Jong Liang, Yi-Ling Lin, Hung-Chih Kuo
• Format: Article
• Language: English
• Published: BMC 2025-08-01
• Subjects: Zika virus; DNA damage; NHEJ; Mutant huntingtin; Huntington’s disease
• Online Access: https://doi.org/10.1186/s13287-025-04539-4

Abstract Background Zika virus (ZIKV) preferentially infects neural progenitor cells (NPCs) and is associated with NPC depletion in neonates. However, the impacts of ZIKV infection on NPCs in the context of neurodegenerative disease such as Huntington’s disease (HD) remains poorly understood. Methods To investigate the effects of ZIKV on NPCs from individuals with HD, induced pluripotent stem cells (iPSCs) derived from HD patients were differentiated into NPCs (HD-iPSC-NPCs) in vitro. The phenotypic characterization of HD-iPSC-NPCs was performed using reverse transcription polymerase chain reaction (RT-PCR), Western blotting, and immunocytochemistry. Additionally, potential interactions between Ku70 and huntingtin were assessed using proximity ligation assay (PLA) and co-immunoprecipitation (co-IP). Results We demonstrated that ZIKV infection increased mutant huntingtin (mHTT) expression through upregulation of SP1 expression. Furthermore, HD-iPSC-NPCs were susceptible to ZIKV-induced DNA double-strand breaks and cell apoptosis due to an impairment of the non-homologous end joining DNA repair pathway, specifically through mHTT-mediated Ku70 degradation. In the HD-iPSC-NPCs, we observed mHTT-Ku70 interaction, which promoted the ubiquitination of Ku70 protein and reduced Ku70-Ku80 heterodimer stability. Conclusions These finding suggest that ZIKV infection exacerbates a known HD-associated DNA damage phenotype, which is present in mHTT-expressing neurons. Our study therefore sheds new light on mechanisms underlying the interplay between ZIKV and HD, highlighting the relevance of viral infections on pathological progression in neurodegenerative disease.