Pathological manifestation of human endogenous retrovirus K in frontotemporal dementia

Katherine Phan, Ying He, YuHong Fu, Nicolas Dzamko, Surabhi Bhatia, Julian Gold, Dominic Rowe, Yazi D. Ke, Lars Ittner, John R. Hodges, Olivier Piguet, Matthew C. Kiernan, Glenda M. Halliday, Woojin Scott Kim

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11 Citations (Scopus)
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Background: Behavioral variant frontotemporal dementia (bvFTD) is a common form of younger-onset dementia with a proportion of cases overlapping pathologically and genetically with amyotrophic lateral sclerosis (ALS). Previous studies have identified that the human endogenous retrovirus K (HERV-K) is elevated in ALS serum and is associated with ALS TDP-43 pathology. In contrast, little is known about HERV-K changes in bvFTD. Here, we investigated the possible role of HERV-K in bvFTD.

Methods: We measured the HERV-K env gene in sporadic bvFTD (N=63), sporadic ALS (N=89) and control (N=21) serum by ddPCR. We also analyzed HERV-K env, by qPCR, and the HERV-K reverse transcriptase protein, by confocal immunofluorescence microscopy, in the disease-affected superior frontal cortex of bvFTD with TDP-43 pathology.

Results: Here, we show that HERV-K env levels are significantly elevated (P=3.5×10-6) in bvFTD compared to control serum, differentiating cases with an AUC value of 0.867. HERV-K env levels are also specifically elevated in the superior frontal cortex of bvFTD with TDP-43 pathology, with the HERV-K reverse transcriptase protein and TDP-43 deposit localized to the neuronal cytoplasm. Furthermore, in a neuronal cell line overexpression of TDP-43 induces HERV-K env transcription.

Conclusions: These results suggest that manifestation of HERV-K is associated with bvFTD TDP-43 pathology. Analysis of HERV-K in bvFTD may provide insight into an unrecognized but targetable perturbed pathology.
Original languageEnglish
Article number60
Pages (from-to)1-11
Number of pages11
JournalCommunications Medicine
Publication statusPublished - 9 Dec 2021

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Copyright the Author(s) 2021. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.


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