Human Endogenous Retrovirus K in Astrocytes Is Altered in Parkinson's Disease

Abstract Background Parkinson's disease (PD) is the most common neurodegenerative movement disease. Human endogenous retroviruses (HERVs) are proviral remnants of ancient retroviral infection of germ cells that now constitute about 8% of the human genome. Under certain disease conditions, HERV genes are activated and partake in the disease process. However, virtually nothing is known about the pathological relationship, if any, between HERV and PD. Objective The objectives of this study were to unravel the pathological relationship between human endogenous retrovirus K (HERV‐K) and PD, determine the localization of HERV‐K in the brain, determine whether HERV‐K levels are altered in PD brain and blood, and examine whether HERV‐K could serve as a biomarker for PD. Methods In situ HERV‐K and glial fibrillary acidic protein (GFAP) expression in the superior frontal and fusiform cortices of PD and control brain were analyzed using immunofluorescence and confocal microscopy. HERV‐K load and copy number in PD and control blood were measured by digital droplet polymerase chain reaction and GFAP by single‐molecule array. HERV‐K load was analyzed in relation to the Hoehn and Yahr Scale and Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III. Results HERV‐K is predominantly expressed in astrocytes and colocalized with astrocytic GFAP, with decreased expression of both HERV‐K and GFAP in PD brain compared with controls. Consistent with this, HERV‐K levels were decreased in PD blood compared with controls and were correlated to blood GFAP levels. HERV‐K levels were inversely correlated to PD severity and duration. Conclusions These findings suggest that HERV‐K is related to astrocyte function and to PD progression, and that HERV‐K could be neuroprotective. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.