Interplay Between Retroviral Element De-repression and Wnt/β-Catenin Pathway in Cellular Models of Parkinson’s Disease

ABSTRACT Parkinson’s disease (PD) is characterized by progressive dopaminergic neurodegeneration driven by complex interactions among oxidative stress, impaired survival signaling, and protein homeostasis disruption. Emerging evidence suggests that endogenous retroelements, including human endogenous retrovirus K (HERV-K), may contribute to neurodegenerative processes; however, their role in PD remains poorly defined. Here, we investigated whether dopaminergic neurotoxic stress induces HERV-K activation and whether modulation of pro-survival signaling pathways influences this response in PD-relevant cellular models. Using undifferentiated SHSY5Y cells and neuron-like retinoic acid–differentiated SHSY5Y cells, we show that exposure to the dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA) induces a rapid and robust transcriptional de-repression of HERV-K Env gene. HERV-K activation occurs early after toxin exposure, scales with the intensity of the insult, and is associated with alterations in oxidative stress defenses, survival signaling pathways, and protein homeostasis. Notably, 6-OHDA treatment promotes the accumulation and cytoplasmic mislocalization of phosphorylated TAR DNA-binding protein 43 (pTDP-43), a pathological feature linked to neurodegenerative proteinopathies. Pharmacological modulation of the Wnt/β-catenin pathway by the natriuretic peptide atrial natriuretic peptide (ANP) significantly attenuates neurotoxin-induced HERV-K activation, restores oxidative stress–related and survival signaling markers, and limits pTDP-43 accumulation and mislocalization. These findings indicate that reinforcement of Wnt/β-catenin dependent protective pathways constrains stress-driven HERV-K de-repression and associated molecular alterations. Overall, this study identifies HERV-K activation as an early stress-responsive feature in PD-like cellular models and supports the existence of a functional interplay between retroelement regulation, survival signaling, and protein homeostasis. Modulation of Wnt/β-catenin signaling may represent a strategy to limit retroelement-associated pathological responses in PD. Competing Interest Statement The authors have declared no competing interest.